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PURPOSE: This study aimed to identify the risk factors for acute pancreatitis (AP) and its impact on outcomes in Polish children treated for ALL. METHODS: The study group included 2303 children receiving intensive chemotherapy for ALL. The group was divided into patients with at least one episode of AP and those who did not develop AP after treatment for ALL. RESULTS: The cumulative incidence of AP in the study group was 4.08%. Older age was an independent risk factor for the development of AP (OR = 1.05; 95%CI = 1.006-1.098; p = 0.03). The overall mortality associated with AP was 2.13%. The probabilities of disease-free survival (p-DFS) and event-free survival (p-EFS) in both subgroups were 0.84 vs. 0.86, log-rank p = 0.65 and 0.75 vs. 0.80, log-rank p = 0.12, respectively. A total of 22 out of 94 patients (23.4%) with AP were re-exposed to asparaginase (ASP) during the subsequent treatment phases. Only one patient re-exposed to ASP (4.5%) developed a second episode of AP. There were no significant differences in p-DFS and p-EFS between patients re-exposed and not re-exposed to asparaginase (0.78 vs. 0.86, log-rank p = 0.27 and 0.63 vs. 0.79, log-rank p = 0.09, respectively). CONCLUSIONS: The incidence of AP in children with ALL is low and related to patients' age. The development of AP does not seem to influence p-DFS and p-EFS in children with ALL. Recurrence of AP after re-exposure to asparaginase in patients with ALL and a history of AP is low (4.5%). Re-exposure to asparaginase after the first episode of AP does not improve either p-DFS or p-EFS in children with ALL.
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Background:Klebsiella pneumoniae is a nosocomial pathogen that causes severe infections in immunocompromised patients. The aim of the study was to conduct a microbiological and clinical analysis of K. pneumoniae infections in children with malignancies or undergoing hematopoietic cell transplantation in Poland. Methods: We conducted a retrospective, multicenter study including children and adolescents under 19 years old treated between 2012 and 2021. We analyzed patients' characteristics, microbiological data, and the outcomes of antibiotic therapy. Results: A total of 9121 newly diagnosed children were treated for malignancy and 1697 pediatric patients underwent hematopoietic cell transplantation. K. pneumoniae infections were diagnosed in 527 patients. Their overall incidence was 4.86% in pediatric hematology and oncology patients and 4.95% in patients who underwent hematopoietic cell transplantation. The incidence of infection was higher in patients with acute leukemia than with solid tumors (7.8% vs. 4.1%; OR = 2.0; 95% CI = 1.6-2.4; p < 0.0001). The most frequent source of infection was in the urinary tract at 55.2%. More than 57% of K. pneumoniae strains were extended-spectrum ß-lactamase-positive and almost 34% were multidrug-resistant. Infections with K. pneumoniae contributed to death in 3.22% of patients. Conclusions: K. pneumoniae is one of the most critical pathogens in children suffering from malignancies or undergoing hematopoietic cell transplantation. The incidence of multidrug-resistant K. pneumoniae strains is increasing and contributing to poor clinical outcome.
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Philadelphia chromosome-positive B-cell precursor acute lymphoblastic leukemia (Ph+ BCPALL) is a high-risk acute lymphoblastic leukemia subtype characterized by the presence of BCR::ABL1 fusion gene. Tyrosine kinase inhibitors (TKIs) combined with chemotherapy are established as the first-line treatment. Additionally, rituximab (RTX), an anti-CD20 monoclonal antibody (mAb) is administered in adult BCP-ALL patients with ≥20% of CD20+ blasts. In this study, we observed a marked prevalence of CD20 expression in patients diagnosed with Ph+ BCP-ALL, indicating a potential widespread clinical application of RTX in combination with TKIs. Consequently, we examined the influence of TKIs on the antitumor effectiveness of anti-CD20 mAbs by evaluating CD20 surface levels and conducting in vitro functional assays. All tested TKIs were found to uniformly downregulate CD20 on leukemic cells, diminishing the efficacy of RTX-mediated complement-dependent cytotoxicity. Interestingly, these TKIs displayed varied effects on NK cell-mediated antibody-dependent cytotoxicity and macrophage phagocytic function. While asciminib demonstrated no inhibition of effector cell functions, dasatinib notably suppressed the anti-CD20-mAb-mediated NK cell cytotoxicity and macrophage phagocytosis of BCP-ALL cells. Dasatinib and ponatinib also decreased NK cell degranulation in vitro. Importantly, oral administration of dasatinib, but not asciminib, compromised NK cell activity within patients' blood, determined by ex vivo degranulation assay. Our results indicate that asciminib might be preferred over other TKIs for combination therapy with anti-CD20 mAbs.
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"Managing Undernutrition in Pediatric Oncology" is a collaborative consensus statement of the Polish Society for Clinical Nutrition of Children and the Polish Society of Pediatric Oncology and Hematology. The early identification and accurate management of malnutrition in children receiving anticancer treatment are crucial components to integrate into comprehensive medical care. Given the scarcity of high-quality literature on this topic, a consensus statement process was chosen over other approaches, such as guidelines, to provide comprehensive recommendations. Nevertheless, an extensive literature review using the PubMed database was conducted. The following terms, namely pediatric, childhood, cancer, pediatric oncology, malnutrition, undernutrition, refeeding syndrome, nutritional support, and nutrition, were used. The consensus was reached through the Delphi method. Comprehensive recommendations aim to identify malnutrition early in children with cancer and optimize nutritional interventions in this group. The statement underscores the importance of baseline and ongoing assessments of nutritional status and the identification of the risk factors for malnutrition development, and it presents tools that can be used to achieve these goals. This consensus statement establishes a standardized approach to nutritional support, aiming to optimize outcomes in pediatric cancer patients.
Subject(s)
Malnutrition , Neoplasms , Child , Child, Preschool , Humans , Child Nutrition Disorders/therapy , Child Nutrition Disorders/diagnosis , Child Nutrition Disorders/diet therapy , Child Nutrition Disorders/prevention & control , Consensus , Delphi Technique , Malnutrition/diagnosis , Malnutrition/therapy , Malnutrition/etiology , Malnutrition/prevention & control , Medical Oncology/standards , Neoplasms/complications , Neoplasms/therapy , Nutrition Assessment , Nutritional Status , Nutritional Support/methods , Pediatrics/standards , Pediatrics/methods , Poland , Societies, MedicalABSTRACT
Background: Patients treated with hemato-oncological malignancies (HO) or undergoing cellular therapies such as hematopoietic stem cell transplantation (HSCT) or chimeric antigen receptor T cells (CAR-T) were significantly affected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Despite the success of SARS-CoV-2 vaccination, immunocompromised patients remain at increased risk for severe coronavirus disease (COVID-19), rendering this group of population a high priority for additional prevention and treatment options. Tixagevimab and Cilgavimab (TIXA/CILGA, AZD7442, Evusheld®) is a combination of two fully human, long-acting monoclonal antibodies. TIXA/CILGA have been approved as pre-exposure prophylaxis and treatment in patients at risk of severe disease with impaired vaccine response. Our objective was to describe the efficacy and safety among immunocompromised pediatric patients. Methods: This was an observational multicenter cohort study of immunocompromised pediatric patients receiving TIXA/CILGA conducted at nine Polish centers of Pediatric Oncology, Hematology and Bone Marrow Transplantation. We analyzed patients in two groups; those treated with HO and those undergoing cellular therapies: HSCT or CAR-T cells. In addition, two other cohorts were identified: patients given TIXA/CILGA as pre-exposure prophylactic and therapeutic intervention. Results: A total of 78 patients were evaluated during the study period: 69 (88.5%) received TIXA/CILGA as pre-exposure prophylaxis and 9 (11.5%) as a treatment strategy. A total of 52 (66.6%) patients were treated with standard chemotherapy at HO departments; 21 (27%) underwent HSCT, and 5 (6.4%) received CAR-T cell therapy. All children with COVID-19 receiving TIXA/CILGA presented a mild degree of severity. The most common clinical manifestations were fever, cough and coryza. At least one adverse event (AE) was reported in two (3.8%) patients excluding standard injection site reactions. Reported AEs were mild or moderate in intensity. One child reported mild myalgia and one reported moderate bone pain and weakness. Conclusions: In our observational multicenter cohort study, we explored the use of TIXA/CILGA as pre-exposure prophylaxis and treatment for COVID-19 among immunocompromised pediatric patients. While our findings suggest a potential benefit in preventing and managing COVID-19 in this vulnerable population, it is important to note the study's non-comparative design. Our results highlight the need for well-designed clinical trials to confirm these observations and further assess the efficacy and safety of TIXA/CILGA in immunocompromised children.
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BACKGROUND: The reports of studies that compare the survival of adolescents and young adults with younger children with acute myeloid leukemia (AML) are contradictory. PATIENTS AND METHODS: We retrospectively analyzed 220 AML patients aged 0-18 years treated in pediatric oncologic centers in Poland from 2015 to 2022. The evaluated group included 31 infants (below 1 year), 91 younger children (1-9.9 years), 59 older children (10-14.9 years), and 39 adolescents (15-18 years). RESULTS: A 5-year overall survival for adolescents was not significantly inferior compared to younger and older children (74.3 ± 7.6% vs. 80.5 ± 4.4% vs. 77.9 ± 5.1, p = 0.243). However, relapse-free survival was lower in adolescents compared to younger children (76.5 ± 7.8% vs. 65.7 ± 9.0%, p = 0.049), and treatment-related mortality tended to be higher (10.3% vs. 4.4%, p = 0.569). In the univariate analysis, high-risk genetics [HR, 2.0 (95% CI 1.1-3.6; p = 0.014)] and a leukocyte count at diagnosis above 100,000/µL [HR, 2.4 (95% CI 1.3-4.6; p = 0.004)] were found to be unfavorable prognostic factors for survival. CONCLUSIONS: Although we have not found that age over 15 years is an unfavorable factor for overall survival, the optimal approach to therapy in adolescents, as in other age groups, is to adjust the intensity of therapy to individual genetic risk and introduce targeted therapies when indicated.
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Diagnostic criteria for juvenile myelomonocytic leukemia (JMML) are currently well defined, however in some patients diagnosis still remains a challenge. Flow cytometry is a well established tool for diagnosis and follow-up of hematological malignancies, nevertheless it is not routinely used for JMML diagnosis. Herewith, we characterized the CD34+ hematopoietic precursor cells collected from 31 children with JMML using a combination of standardized EuroFlow antibody panels to assess the ability to discriminate JMML cells from normal/reactive bone marrow cell as controls (n=29) or from cells of children with other hematological diseases mimicking JMML (n=9). CD34+ precursors in JMML showed markedly reduced B-cell and erythroid-committed precursors compared to controls, whereas monocytic and CD7+ lymphoid precursors were significantly expanded. Moreover, aberrant immunophenotypes were consistently present in CD34+ precursors in JMML, while they were virtually absent in controls. Multivariate logistic regression analysis showed that combined assessment of the number of CD34+CD7+ lymphoid precursors and CD34+ aberrant precursors or erythroid precursors had a great potential in discriminating JMMLs versus controls. Importantly our scoring model allowed highly efficient discrimination of truly JMML versus patients with JMML-like diseases. In conclusion, we show for the first time that CD34+ precursors from JMML patients display a unique immunophenotypic profile which might contribute to a fast and accurate diagnosis of JMML worldwide by applying an easy to standardize single eight-color antibody combination.
Subject(s)
Leukemia, Myelomonocytic, Juvenile , Child , Humans , Leukemia, Myelomonocytic, Juvenile/diagnosis , Leukemia, Myelomonocytic, Juvenile/genetics , Flow Cytometry , Antigens, CD34/genetics , Monocytes/pathologyABSTRACT
The most common complications related to the treatment of childhood acute lymphoblastic leukemia (ALL) are infections. The aim of the study was to analyze the incidence and mortality rates among pediatric patients with ALL who were treated in 17 Polish pediatric hematology centers in 2020-2021 during the pandemic. Additionally, we compared these results with those of our previous study, which we conducted in the years 2012-2017. The retrospective analysis included 460 patients aged 1-18 years with newly diagnosed ALL. In our study, 361/460 (78.5%) children were reported to have microbiologically documented bacterial infections during chemotherapy. Ten patients (2.8%) died due to sepsis. Fungal infections were reported in 99 children (21.5%), of whom five (5.1%) died due to the infection. We especially observed an increase in bacterial infections during the pandemic period compared to the previous study. The directions of our actions should be to consider antibiotic prophylaxis, shorten the duration of hospitalization, and educate parents and medical staff about complications (mainly infections) during anticancer therapy. It is necessary to continue clinical studies evaluating infection prophylaxis to improve outcomes in childhood ALL patients.
Subject(s)
Bacterial Infections , Mycoses , Precursor Cell Lymphoblastic Leukemia-Lymphoma , Child , Humans , Retrospective Studies , Incidence , Poland/epidemiology , Pandemics , Bacterial Infections/microbiology , Precursor Cell Lymphoblastic Leukemia-Lymphoma/complications , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Precursor Cell Lymphoblastic Leukemia-Lymphoma/epidemiology , Mycoses/complicationsABSTRACT
BACKGROUND: The FMS-like tyrosine kinase 3 (FLT3) gene mutated in 10-15% of pediatric acute myeloid leukemia (AML) is associated with an inferior outcome. The aim of the study was to analyze the outcome and characteristics of FLT3-ITD-positive pediatric AML. METHODS: We retrospectively analyzed the nationwide pediatric AML database from between 2005 and 2022. FLT3-ITD was found in 54/497 (10.7%) patients with available analysis. Three consecutive treatment protocols were used (AML-BFM 2004 Interim, AML-BFM 2012 Registry, AML-BFM 2019 recommendations). RESULTS: Probabilities of 5-year overall (OS), event-free (EFS) and relapse-free survival were significantly lower in the FLT3-ITD-positive patients compared to FLT3-ITD-negative (0.54 vs. 0.71, p = 0.041; 0.36 vs. 0.59, p = 0.0004; 0.47 vs. 0.70, p = 0.0029, accordingly). An improvement in the outcome was found in the analyzed period of time, with a trend of better survival in patients treated under the AML-BFM 2012 and AML-BFM 2019 protocols compared to the AML-BFM 2004 protocol (5-year EFS 0.52 vs. 0.27, p = 0.069). There was a trend of improved outcomes in patients treated with FLT3 inhibitors (n = 9, 2-year EFS 0.67 vs. 0.33, p = 0.053) and those who received stem cell transplantation (SCT) (n = 26; 5-year EFS 0.70 vs. 0.27, p = 0.059). The co-occurrence of the WT1 mutation had a dismal impact on the prognosis (5-year EFS 0.23 vs. 0.69, p = 0.002), while the NPM1 mutation improved survival (5-year OS 1.0 vs. 0.44, p = 0.036). CONCLUSIONS: It seems that SCT and FLT3 inhibitors have a beneficial impact on the prognosis. Additional genetic alterations, like the WT1 and NPM1 mutations, significantly influence the outcome.
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Presence of minimal residual disease (MRD), detected by flow cytometry, is an important prognostic biomarker in the management of B-cell precursor acute lymphoblastic leukemia (BCP-ALL). However, data-analysis remains mainly expert-dependent. In this study, we designed and validated an Automated Gating & Identification (AGI) tool for MRD analysis in BCP-ALL patients using the two tubes of the EuroFlow 8-color MRD panel. The accuracy, repeatability, and reproducibility of the AGI tool was validated in a multicenter study using bone marrow follow-up samples from 174 BCP-ALL patients, stained with the EuroFlow BCP-ALL MRD panel. In these patients, MRD was assessed both by manual analysis and by AGI tool supported analysis. Comparison of MRD levels obtained between both approaches showed a concordance rate of 83%, with comparable concordances between MRD tubes (tube 1, 2 or both), treatment received (chemotherapy versus targeted therapy) and flow cytometers (FACSCanto versus FACSLyric). After review of discordant cases by additional experts, the concordance increased to 97%. Furthermore, the AGI tool showed excellent intra-expert concordance (100%) and good inter-expert concordance (90%). In addition to MRD levels, also percentages of normal cell populations showed excellent concordance between manual and AGI tool analysis. We conclude that the AGI tool may facilitate MRD analysis using the EuroFlow BCP-ALL MRD protocol and will contribute to a more standardized and objective MRD assessment. However, appropriate training is required for the correct analysis of MRD data.
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PURPOSE: The International Berlin-Frankfurt-Münster (BFM) study group conducted a study on pediatric acute lymphoblastic leukemia (ALL). Minimal residual disease (MRD) was assessed using flow cytometry (FCM), and the impact of early intensification and methotrexate (MTX) dose on survival was evaluated. PATIENTS AND METHODS: We included 6,187 patients younger than 19 years. MRD by FCM refined the risk group definition previously used in the ALL intercontinental-BFM 2002 study on the basis of age, WBC count, unfavorable genetic aberrations, and treatment response measured morphologically. Patients at intermediate risk (IR) and high risk (HR) were randomly assigned to protocol augmented protocol I phase B (IB) versus IB regimen. MTX doses of 2 versus 5 g/m2 every 2 weeks, four times, were evaluated in precursor B-cell-ALL (pcB-ALL) IR. RESULTS: The 5-year event-free survival (EFS ± SE) and overall survival (OS ± SE) rates were 75.2% ± 0.6% and 82.6% ± 0.5%, respectively. Their values in risk groups were standard risk (n = 624), 90.7% ± 1.4% and 94.7% ± 1.1%; IR (n = 4,111), 77.9% ± 0.7% and 85.7% ± 0.6%; and HR (n = 1,452), 60.8% ± 1.5% and 68.4% ± 1.4%, respectively. MRD by FCM was available in 82.6% of cases. The 5-year EFS rates in patients randomly assigned to protocol IB (n = 1,669) and augmented IB (n = 1,620) were 73.6% ± 1.2% and 72.8% ± 1.2%, respectively (P = .55), while those in patients receiving MTX doses of 2 g/m2 (n = 1,056) and MTX 5 g/m2 (n = 1,027) were 78.8% ± 1.4% and 78.9% ± 1.4%, respectively (P = .84). CONCLUSION: The MRDs were successfully assessed using FCM. An MTX dose of 2 g/m2 was effective in preventing relapse in non-HR pcB-ALL. Augmented IB showed no advantages over the standard IB.[Media: see text].
Subject(s)
Precursor B-Cell Lymphoblastic Leukemia-Lymphoma , Precursor Cell Lymphoblastic Leukemia-Lymphoma , Child , Humans , Infant , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Methotrexate/therapeutic use , Risk Factors , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Disease-Free Survival , Treatment OutcomeABSTRACT
Venetoclax, the best established BH3-mimetic, is a practice-changing proapoptotic drug in blood cancers in adults. In paediatrics the data are fewer but exciting results were recently presented in relapsed or refractory leukaemias demonstrating significant clinical activity. Importantly, the in-terventions could be potentially molecularly guided as vulnerabilities to BH3-mimetics were re-ported. Currently venetoclax is not incorporated into paediatric treatment schedules in Poland but it has been already used in patients that failed conventional therapy in Polish paediatric haemato-oncology departments. The aim of the study was to gather clinical data and correlates of all paediatric patients treated so far with venetoclax in Poland. We set out to gather this experience to help choose the right clinical context for the drug and stimulate further research. The questionnaire regarding the use of venetoclax was sent to all 18 Polish paediatric haemato-oncology centres. The data as available in November 2022 were gathered and analysed for the diagnoses, triggers for the intervention, treatment schedules, outcomes and molecular associations. We received response from 11 centres, 5 of which administered venetoclax to their patients. Clinical benefit, in most cases consistent with hematologic complete remission (CR), was reported in 5 patients out of ten, whereas 5 patient did not show clinical benefit from the intervention. Importantly, patients with CR included subtypes expected to show venetoclax vulnerability, such as poor-prognosis ALL with TCF::HLF fusion. We believe BH3-mimetics have clinical activity in children and should be available to pae-diatric haemato-oncology practitioners in well-selected applications.
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Introduction: In 2020, the new nationwide protocol of prophylaxis in Polish plasma-derived FVIII (pdFVIII) previously treated patients (PTPs) with severe hemophilia A (sHA) was introduced, resulting in the necessity of switching from pdFVIII to recombinant FVIII (octocog-alpha; rFVIII). The study aimed to: (1) assess the safety of switching from pdFVIII to rFVIII, (2) assess the safety and efficacy of pharmacokinetically based (PK-based) personalized prophylaxis in severe hemophilia A. Patients and methods: 151 children and adolescents receiving prophylaxis with a standard dose (40â U/kg 3 x weekly) of pdFVIII were included in this study. Annualized bleeding rate (ABR) and annualized joint bleeding rate (AJBR) were analyzed for all patients before enrollment. Using myPKFiT application, pharmacokinetic (PK) analysis followed by the selection of the optimal model of prophylaxis was performed in all patients. Two possible models of prophylaxis (standard-dose rFVIII versus PK-based rFVIII) were discussed, with parents leaving the choice to their decision. Parents reported all episodes of bleeds. Screening for inhibitor was performed every 3 months. ABR and AJBR were prospectively analyzed again after a minimum follow-up time of 26 weeks. Results: 141/151 (93.4%) patients completed the study. 34 patients decided to continue standard prophylaxis with rFVIII (Group I), whereas 107 were switched to PK-based prophylaxis (Group II). The risk of inhibitor development could be assessed in 137/151 (90.7%) patients. Only 2/137 (1.47%) patients (both on PK-based prophylaxis) developed low-titer inhibitor with its spontaneous elimination. The retrospective analysis of bleeds during the last 12 months of standard pdFVIII prophylaxis revealed that patients who decided to continue standard prophylaxis had historically lower ABR and AJBR than those who started PK-based personalized prophylaxis. After a minimum of 26 weeks, ABR and AJBR improved significantly in both groups. There was no significant difference in ABR and AJBR between Group I and Group II during the follow-up period. However, the rate of reduction of ABR and AJBR was higher in patients on PK-based personalized prophylaxis. Conclusion: (1) Switching from pdFVIII to rFVIII (octocog-alpha) in PTPs with sHA is safe, (2) PK-based personalized prophylaxis may decrease ABR and AJBR in children and adolescents with sHA.
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Acute P./myeloid leukemia post cytotoxic therapy (AML-pCT) is rare complication of cancer treatment in childhood. The objective of the study was to identify clinical characteristics and provide an analysis of the outcomes in pediatric AML-pCT. We retrospectively analyzed the data of 40 children with AML-pCT, treated from 2005 to 2020 within the Polish Pediatric Leukemia and Lymphoma Study Group. The most common primary malignancies were acute lymphoblastic leukemia (32.5%) and brain tumors (20%). The median latency period was 2.9 years (range: 0.7-12.9). Probabilities of overall (OS), event-free (EFS), and relapse-free survival (RFS) in the whole cohort were 0.49 ± 0.08, 0.43 ± 0.08, and 0.64 ± 0.10, respectively. Significant improvements in outcomes were observed in patients treated from 2015-2022 (two induction cycles followed by stem cell transplantation-SCT in 69% of patients) compared to 2005-2014 (four induction cycles followed by SCT in 49% of patients). The probability of EFS increased from 0.30 ± 0.10 to 0.67 ± 0.12 (p = 0.07) and RFS increased from 0.46 ± 0.11 to 1.0 (p = 0.01). The poorest outcome (OS and EFS 0.25 ± 0.20) was in AML post brain tumor, mainly due to deaths from toxicities. To conclude, treatment results achieved in patients with AML-pCT treated from 2015-2022, with two induction cycles followed by immediate SCT, were better than those reported by other authors, and comparable to the results in de novo AML.
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Although hematologic malignancies (HM) are no longer considered exclusively sporadic, additional awareness of familial cases has yet to be created. Individuals carrying a (likely) pathogenic germline variant (e.g., in ETV6, GATA2, SAMD9, SAMD9L, or RUNX1) are at an increased risk for developing HM. Given the clinical and psychological impact associated with the diagnosis of a genetic predisposition to HM, it is of utmost importance to provide high-quality, standardized patient care. To address these issues and harmonize care across Europe, the Familial Leukemia Subnetwork within the ERN PaedCan has been assigned to draft an European Standard Clinical Practice (ESCP) document reflecting current best practices for pediatric patients and (healthy) relatives with (suspected) familial leukemia. The group was supported by members of the German network for rare diseases MyPred, of the Host Genome Working Group of SIOPE, and of the COST action LEGEND. The ESCP on familial leukemia is proposed by an interdisciplinary team of experts including hematologists, oncologists, and human geneticists. It is intended to provide general recommendations in areas where disease-specific recommendations do not yet exist. Here, we describe key issues for the medical care of familial leukemia that shall pave the way for a future consensus guideline: (i) identification of individuals with or suggestive of familial leukemia, (ii) genetic analysis and variant interpretation, (iii) genetic counseling and patient education, and (iv) surveillance and (psychological) support. To address the question on how to proceed with individuals suggestive of or at risk of familial leukemia, we developed an algorithm covering four different, partially linked clinical scenarios, and additionally a decision tree to guide clinicians in their considerations regarding familial leukemia in minors with HM. Our recommendations cover, not only patients but also relatives that both should have access to adequate medical care. We illustrate the importance of natural history studies and the need for respective registries for future evidence-based recommendations that shall be updated as new evidence-based standards are established.
Subject(s)
Genetic Predisposition to Disease , Leukemia , Humans , Child , Genetic Counseling , Germ-Line Mutation , Transcription Factors , Intracellular Signaling Peptides and ProteinsABSTRACT
The development of a second malignancy after the diagnosis of childhood acute lymphoblastic leukemia (ALL) is a rare event. Certain second malignancies have been linked with specific elements of leukemia therapy, yet the etiology of most second neoplasms remains obscure and their optimal management strategies are unclear. This is a first comprehensive report of non-Hodgkin lymphomas (NHLs) following pediatric ALL therapy, excluding stem-cell transplantation. We analyzed data of patients who developed NHL following ALL diagnosis and were enrolled in 12 collaborative pediatric ALL trials between 1980-2018. Eighty-five patients developed NHL, with mature B-cell lymphoproliferations as the dominant subtype (56 of 85 cases). Forty-six of these 56 cases (82%) occurred during or within 6 months of maintenance therapy. The majority exhibited histopathological characteristics associated with immunodeficiency (65%), predominantly evidence of Epstein-Barr virus-driven lymphoproliferation. We investigated 66 cases of post-ALL immunodeficiency-associated lymphoid neoplasms, 52 from our study and 14 additional cases from a literature search. With a median follow-up of 4.9 years, the 5-year overall survival for the 66 patients with immunodeficiency-associated lymphoid neoplasms was 67.4% (95% confidence interval [CI], 56-81). Five-year cumulative risks of lymphoid neoplasm- and leukemia-related mortality were 20% (95% CI, 10.2-30) and 12.4% (95% CI, 2.7-22), respectively. Concurrent hemophagocytic lymphohistiocytosis was associated with increased mortality (hazard ratio, 7.32; 95% CI, 1.62-32.98; P = .01). A large proportion of post-ALL lymphoid neoplasms are associated with an immunodeficient state, likely precipitated by ALL maintenance therapy. Awareness of this underrecognized entity and pertinent diagnostic tests are crucial for early diagnosis and optimal therapy.
Subject(s)
Epstein-Barr Virus Infections , Lymphoma, Non-Hodgkin , Lymphoma , Neoplasms, Second Primary , Precursor Cell Lymphoblastic Leukemia-Lymphoma , Child , Humans , Herpesvirus 4, Human , Epstein-Barr Virus Infections/complications , Epstein-Barr Virus Infections/diagnosis , Lymphoma/complications , Lymphoma, Non-Hodgkin/pathology , Precursor Cell Lymphoblastic Leukemia-Lymphoma/therapy , Precursor Cell Lymphoblastic Leukemia-Lymphoma/complicationsABSTRACT
We analyzed the pattern of whole-genome copy number alterations (CNAs) and their association with the kinetics of blast clearance during the induction treatment among 195 pediatric patients with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) who displayed intermediate or high levels of minimal residual disease (MRD). Using unsupervised hierarchical clustering of CNAs > 5 Mbp, we dissected three clusters of leukemic samples with distinct kinetics of blast clearance [A - early slow responders (n=105), B - patients with persistent leukemia (n=24), C - fast responders with the low but detectable disease at the end of induction (n=66)] that corresponded with the patients' clinical features, the microdeletion profile,the presence of gene fusions and patients survival. Low incidence of large CNAs and chromosomal numerical aberrations occurred in cluster A which included ALL samples showing recurrent microdeletions within the genes encoding transcription factors (i.e., IKZF1, PAX5, ETV6, and ERG), DNA repair genes (XRCC3 and TOX), or harboring chromothriptic pattern of CNAs. Low hyperdiploid karyotype with trisomy 8 or hypodiploidy was predominantly observed in cluster B. Whereas cluster C included almost exclusively high-hyperdiploid ALL samples with concomitant mutations in RAS pathway genes. The pattern of CNAs influences the kinetics of leukemic cell clearance and selected aberrations affecting DNA repair genes may contribute to BCP-ALL chemoresistance.
Subject(s)
Precursor B-Cell Lymphoblastic Leukemia-Lymphoma , Precursor Cell Lymphoblastic Leukemia-Lymphoma , Child , Humans , DNA Copy Number Variations , Kinetics , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/genetics , Neoplasm, Residual , Chromosome Aberrations , Transcription Factors/geneticsABSTRACT
Background: Gemtuzumab ozogamicin (GO), one of the first targeted drugs used in oncology, consists of an anti-cluster of differentiation 33 (CD33) monoclonal antibody bound to a derivative of cytotoxic calicheamicin. After the drug withdrawn in 2010 due to a significantly higher rate of early deaths, GO regained approval in 2017 for the treatment of newly diagnosed, refractory, or relapsed acute myeloid leukemia (AML) in adults and children over 15 years of age. The objective of the study was a retrospective analysis of clinical characteristics, treatment outcomes, and GO toxicity profile in children with primary refractory or relapsed (R/R) AML treated in Poland from 2008 to 2022. Methods: Data were collected through the Polish Registry of Acute Myeloid Leukemia. From January 2008 to December 2022, 35 children with R/R AML were treated with GO in seven centers of the Polish Pediatric Leukemia and Lymphoma Study Group. Results: Most of the children (30 of 35) received only one GO cycle in combination with various chemotherapy cycles (IDA-FLA, DOXO-FLA, FLA, FLAG, and others). Eighteen children (51%) achieved complete remission (CR), 14 did not respond to treatment, and three progressed. GO therapy was followed by allogeneic hematopoietic stem cell transplantation (allo-HSCT) in 18 children in CR. The 5-year overall survival (OS) after GO therapy was 37.1% ± 8.7% for the total cohort. There was a trend toward a superior outcome in patients with strong expression of CD33 expression (over 50% positive cells) compared with that in patients with lower expression of CD33 (OS, 41.2% ± 11.9% versus 27.8% ± 13.2%; p = 0.5; 5-year event-free survival, 35.4% ± 11.6% versus 25.7% ± 12.3%; p = 0.5, respectively). Children under 15 years have better outcome (OS, 34.9% ± 10.4% versus 30% ± 14.5%, p = 0.3). The most common adverse events were bone marrow aplasia, fever of unknown origin, infections, and elevated liver enzyme elevation. Sinusoidal obstruction syndrome occurred in two children. Conclusions: The use of GO in severely pretreated children, including those under 15 years of age, with previous failure of AML treatment is a feasible and effective bridging therapy to allo-HSCT with an acceptable toxicity profile.
Subject(s)
Leukemia, Myeloid, Acute , Lymphoma , Adult , Humans , Child , Gemtuzumab/therapeutic use , Poland , Retrospective Studies , Leukemia, Myeloid, Acute/drug therapy , Pathologic Complete ResponseABSTRACT
Introduction: This study aimed to present the clinical features and results of treatment of patients diagnosed with refractory or relapsed acute myeloid leukaemia (AML) in Polish Paediatric Leukaemia/Lymphoma Study Group (PPL/LSG) institutions, treated in accordance with the Protocol Acute Myeloid Leukaemia Berlin-Frankfurt-Munster 2012, as their first-line therapy. Material and methods: The outcome data of 10 patients with refractory AML (median age 9.5 years) and 30 with relapsed AML (median age 12 years) were analysed retrospectively. Re-induction was usually based on idarubicin, fludarabine, and cytarabine along with allogeneic haematopoietic stem cell transplant (allo-HSCT) in 5 patients with refractory AML and 7 relapsed AML children. Results: 37.5% (3/8) of refractory AML patients achieved second complete remission second complete remission (CRII). One of ten patients (1/10; 10%) was alive and stayed in complete remission for 34 months after the allo-HSCT. The probability of 3-year event-free survival (pEFS) in this group was 0.125 ±0.11. In the group of relapsed AML patients, the CRII was achieved in 9 patients (34%), and the probability of survival was: pEFS = 0.24 ±0.08; probability overall survival (pOS) = 0.34 ±0.09, with significantly better results achieved in patients who underwent allo-HSCT (pOS = 0.54 ±0.14 vs. 0.08 ±0.08, p < 0.0001). Conclusions: The prognosis of refractory AML and the first AML recurrence in children who were first-line treated in PPL/LSG centres according to Protocol Acute Myeloid Leukaemia Berlin-Frankfurt-Munster 2012 is poor. Failures of re-induction treatment particularly result from difficulties in achieving remission. Allogeneic HSCT improves prognosis in children with refractory and first recurrent AML, under the condition it is performed in complete remission. Novel therapeutic approaches are needed to increase the remission rate and improve the outcomes.
ABSTRACT
The optimal bridging therapy before CAR-T cell infusion in pediatric relapsed or refractory B-cell precursor acute lymphoblastic leukemia (r/r BCP-ALL) still remains an open question. The administration of blinatumomab prior to CAR-T therapy is controversial since a potential loss of CD19+ target cells may negatively impact the activation, persistence, and, as a consequence, the efficacy of subsequently used CAR-T cells. Here, we report a single-center experience in seven children with chemorefractory BCP-ALL treated with blinatumomab before CAR-T cell therapy either to reduce disease burden before apheresis (six patients) or as a bridging therapy (two patients). All patients responded to blinatumomab except one. At the time of CAR-T cell infusion, all patients were in cytological complete remission (CR). Four patients had low positive PCR-MRD, and the remaining three were MRD-negative. All patients remained in CR at day +28 after CAR-T infusion, and six out of seven patients were MRD-negative. With a median follow-up of 497 days, four patients remain in CR and MRD-negative. Three children relapsed with CD19 negative disease: two of them died, and one, who previously did not respond to blinatumomab, was successfully rescued by stem cell transplant. To conclude, blinatumomab can effectively lower disease burden with fewer side effects than standard chemotherapeutics. Therefore, it may be a valid option for patients with high-disease burden prior to CAR-T cell therapy without clear evidence of compromising efficacy; however, further investigations are necessary.