Hematopoietic cell transplant for reversal of liver fibrosis in a pediatric patient with erythropoietic protoporphyria.

BACKGROUND: EPP is a rare disorder of heme biosynthesis in which patients present with disabling photosensitivity. A subset of patients develop severe liver disease with progressive liver failure necessitating an OLT. A HCT can potentially cure EPP by replacing the native bone marrow, which is the primary site of heme synthesis. However, due to concerns for inherent risks of treatment-related toxicities, the use of HCT has been reserved for patients undergoing an OLT to avoid disease recurrence in the hepatic graft. Data for HCT in EPP are lacking, particularly in the pediatric population. CASE (METHODS/RESULTS): We present the case of a 12-year-old patient with EPP photosensitivity and cirrhosis, whom we successfully treated with pre-emptive allogeneic HCT, significantly improving the patient's quality of life. We used a matched-unrelated donor bone marrow-derived graft. Our patient achieved full donor peripheral blood chimerism and has not had any evidence of GVHD. In addition to resolution of photosensitivity, our patient had reversal of liver fibrosis which we feel was largely due to intervention at an early stage of compensated cirrhosis. CONCLUSION: Our case highlights the successful application of a known RIC regimen to this rare disorder that was well tolerated with sustained donor engraftment. It also emphasizes the importance of timing for HCT in patients with EPP and liver fibrosis. HCT should be considered early in pediatric patients with EPP-hepatopathy to prevent progression to liver failure and need for OLT with lifelong immunosuppression.

Encouraging Outcomes of Alternate Donor Hematopoietic Stem Cell Transplant in Pediatric High-risk/Relapsed Leukemias: A Single Center Experience.

Outcomes of high-risk and relapsed pediatric acute leukemias continue to be suboptimal. Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative modality. However, <30% of patients have matched sibling donors available. Hence, alternate donors (matched unrelated and haploidentical) are being used to improve outcomes. We retrospectively analyzed our data of all children with high-risk/relapsed acute leukemias who underwent alternate donor HSCT at our center from April 2015 to July 2020. A total of 15 patients were included-3 underwent matched unrelated and 12 underwent haploidentical HSCT. Before HSCT, all patients were in complete remission (CR): CR1-1, CR2-11, and CR3-3. All patients engrafted except one. Median time to neutrophil and platelet engraftment was 15 and 16 days, respectively. There were 3 transplant related mortalities. One patient was lost to follow-up. Remaining 11 patients remain in remission and are alive. The cumulative incidence of acute graft versus host disease was 57.1% and of chronic graft versus host disease was 21.4%. Overall survival was 80% and the event-free survival was 73.3%. The median follow-up of alive patients was 775 days (range: 333 to 2077 d). Our experience shows encouraging outcomes using alternate donor HSCT for these patients from developing world.

Allogeneic Hematopoietic Stem Cell Transplant Offer Good Outcomes in Pediatric Aplastic Anemia: Experience From Developing World.

Between 2014 and 2020, 31 patients with severe aplastic anemia (SAA) underwent full match allogeneic hematopoietic stem cell transplantation at our center. Of the 31 patients with SAA, 19 had acquired aplastic anemia, 2 had Diamond Blackfan anemia and 10 had Fanconi anemia. Donors were either matched sibling (n=29), related donors (n=2), or unrelated donors (n=3). Peripheral blood stem cells were the graft source in all the cases except 1. Fludarabine-based reduced intensity conditioning was used in all except for patients with a diagnosis of Diamond Blackfan anemia. All patients except 1 achieved hematologic recovery in the form of neutrophil engraftment at 13 days (range, 9 to 17), whereas platelet engraftment occurred at 14 days (range, 10 to 18). Graft versus host disease (GvHD) prophylaxis consisted of cyclosporine and methotrexate ±antithymocyte globulin (horse/rabbit). Acute GvHD developed in 12.9% patients, whereas no patients developed chronic GvHD till the time of last follow-up. The 2-year overall survival for the entire cohort was 93.21±4.6%. In patients with SAA, allogeneic stem cell transplant using fludarabine-based conditioning regimens are very well tolerated and have excellent outcomes in a full match setting.

Haploidentical Stem Cell Transplant With Post-transplant Cyclophosphamide for Chediak-Higashi Syndrome: A Very Rare Case Report.

Chediak-Higashi syndrome is a rare immunodeficiency disorder for which hematopoietic stem cell transplant (HSCT) is the only curative treatment option. HSCT only corrects the hematologic and immunologic manifestations of the disease but neurologic complications may still progress after transplant. Haploidentical HSCT (haplo-HSCT) has evolved as a feasible alternative for patients with primary immunodeficiency. More recently, there has been use of haplo-HSCT with post-transplant cyclophosphamide. However, only 4 cases of Chediak-Higashi syndrome have been reported using this approach. Here, the authors describe a case of a 17-month-old boy who was successfully treated by haplo-HSCT with reduced-toxicity conditioning (fludarabine/treosulfan/melphalan) and post-transplant cyclophosphamide.

Transcriptional Regulation of JARID1B/KDM5B Histone Demethylase by Ikaros, Histone Deacetylase 1 (HDAC1), and Casein Kinase 2 (CK2) in B-cell Acute Lymphoblastic Leukemia.

Impaired function of the Ikaros (IKZF1) protein is associated with the development of high-risk B-cell precursor acute lymphoblastic leukemia (B-ALL). The mechanisms of Ikaros tumor suppressor activity in leukemia are unknown. Ikaros binds to the upstream regulatory elements of its target genes and regulates their transcription via chromatin remodeling. Here, we report that Ikaros represses transcription of the histone H3K4 demethylase, JARID1B (KDM5B). Transcriptional repression of JARID1B is associated with increased global levels of H3K4 trimethylation. Ikaros-mediated repression of JARID1B is dependent on the activity of the histone deacetylase, HDAC1, which binds to the upstream regulatory element of JARID1B in complex with Ikaros. In leukemia, JARID1B is overexpressed, and its inhibition results in cellular growth arrest. Ikaros-mediated repression of JARID1B in leukemia is impaired by pro-oncogenic casein kinase 2 (CK2). Inhibition of CK2 results in increased binding of the Ikaros-HDAC1 complex to the promoter of JARID1B, with increased formation of trimethylated histone H3 lysine 27 and decreased histone H3 Lys-9 acetylation. In cases of high-risk B-ALL that carry deletion of one Ikaros (IKZF1) allele, targeted inhibition of CK2 restores Ikaros binding to the JARID1B promoter and repression of JARID1B. In summary, the presented data suggest a mechanism through which Ikaros and HDAC1 regulate the epigenetic signature in leukemia: via regulation of JARID1B transcription. The presented data identify JARID1B as a novel therapeutic target in B-ALL and provide a rationale for the use of CK2 inhibitors in the treatment of high-risk B-ALL.

Targeting casein kinase II restores Ikaros tumor suppressor activity and demonstrates therapeutic efficacy in high-risk leukemia.

Ikaros (IKZF1) is a tumor suppressor that binds DNA and regulates expression of its target genes. The mechanism of Ikaros activity as a tumor suppressor and the regulation of Ikaros function in leukemia are unknown. Here, we demonstrate that Ikaros controls cellular proliferation by repressing expression of genes that promote cell cycle progression and the phosphatidylinositol-3 kinase (PI3K) pathway. We show that Ikaros function is impaired by the pro-oncogenic casein kinase II (CK2), and that CK2 is overexpressed in leukemia. CK2 inhibition restores Ikaros function as transcriptional repressor of cell cycle and PI3K pathway genes, resulting in an antileukemia effect. In high-risk leukemia where one IKZF1 allele has been deleted, CK2 inhibition restores the transcriptional repressor function of the remaining wild-type IKZF1 allele. CK2 inhibition demonstrated a potent therapeutic effect in a panel of patient-derived primary high-risk B-cell acute lymphoblastic leukemia xenografts as indicated by prolonged survival and a reduction of leukemia burden. We demonstrate the efficacy of a novel therapeutic approach for high-risk leukemia: restoration of Ikaros tumor suppressor activity via inhibition of CK2. These results provide a rationale for the use of CK2 inhibitors in clinical trials for high-risk leukemia, including cases with deletion of one IKZF1 allele.

Overall and Event Free Survival of Childhood Cancer - Report From a Hospital-based Cancer Registry in Northern India, 2013-21.

OBJECTIVE: Using data from a hospital-based cancer registry (HBCR) in the private sector in Northern India, we provide overall survival (OS) and event-free survival (EFS) for childhood cancer patients. METHODS: All newly diagnosed childhood (age <18 years) cancer patients in our HBCR registered between March 1, 2013 till July 31, 2021 were eligible. 3-year and 5-year OS (death was an event), EFSc (death, progression/relapse was an event), and EFSa (death, progression/relapse, abandonment of treatment was an event) were calculated using the Kaplan-Meier method. Regression analysis was done to see their association with demographic, diagnostic and treatment variables. RESULTS: 705 newly diagnosed children (36.2% female) with cancer were registered. Common cancers were leukemias (26%), CNS tumors (20%) and bone tumors (16%). 202 (28.6%) had experienced an event at median follow up of 1.95 years (range 0-8.14 years), which included 23 (3.3%) who abandoned treatment. The 3-year OS, EFSc, EFSa were 70.8%, 64.4% and 63.6%, respectively. Correspondingly, 5-year OS, EFSc, EFSa were 66%, 58.6% and 57.5%, respectively. There was no significant difference by age group, gender, nationality, and if cancer directed treatment initiated elsewhere. The OS, EFSa and EFSc by the main and the extended International Childhood Cancer Classification categories varied significantly (P<0.001). CONCLUSION: We add more recent registry-based OS data on childhood cancer in India and present the first estimates on EFS.

Impact of Conditioning Regimen and Graft-versus-Host Disease Prophylaxis on The Outcome of Haploidentical Peripheral Blood Stem Cell Transplantation for High-Risk Severe Aplastic Anemia in Children and Young Adults: A Report from the Pediatric Severe Aplastic Anemia Consortium of India.

Allogenic hematopoietic cell transplantation (HCT) is the best curative approach for patients with severe aplastic anemia (SAA). The outcomes of HCT from haploidentical family donors (HFDs) have improved, making it a feasible option for patients lacking an HLA-identical donor. However, data on HFD-HCT for younger patients with SAA is sparse. In this multicenter retrospective study, we evaluated the outcomes of 79 patients undergoing HFD-HCT for SAA. All the patients were heavily pretransfused, the median time to HCT was >12 months, and 67% had failed previous therapies. Conditioning was based on fludarabine (Flu)-cyclophosphamide (Cy)-antithymocyte globulin (ATG)/total body irradiation (TBI) with or without thiotepa/melphalan (TT/Mel). Post-transplantation Cy (PTCy) and calcineurin inhibitors (CNIs)/sirolimus were used as graft-versus-host disease (GVHD) prophylaxis with or without abatacept. The rate of primary graft failure (PGF) was 16.43% overall, lower in patients conditioned with TT/Mel. The incidences of acute and chronic GVHD were 26.4% and 18.9%, respectively. At a median follow-up of 48 months, the overall survival (OS) and event-free survival (EFS) were 61.6% and 58.1%, respectively. Both OS and EFS were better in the TT/Mel recipients and with abatacept as GVHD prophylaxis. On multivariate analysis, the use of abatacept was found to favorably impact the outcome variables, including GVHD and EFS. Our study suggests that PTCy-based HFD-HCT is a reasonable option for young patients with high-risk SAA, in whom optimization of conditioning and GVHD prophylaxis might further improve outcomes.

Multicenter Outcome of Hematopoietic Stem Cell Transplantation for Primary Immune Deficiency Disorders in India.

Background: Hematopoietic stem cell transplantation (HSCT) is the curative option for many primary immune deficiency disorders (PID). In the last 5 years, increased awareness, availability of diagnostics based on flow cytometry, genetic testing, improved supportive care, use of reduced toxicity conditioning, and success of haploidentical donor HSCT have improved access to HSCT for children with PID in India. We present results on children with PID who underwent HSCT across India and the factors that influenced outcome. Patients and Methods: We collected retrospective data on the outcome of HSCT for PID from seven centers. We analyzed the impact of the type of PID, conditioning regimen, time period of HSCT- before or after January 2016, graft versus host disease prophylaxis, cause of mortality and overall survival. Results: A total of 228 children underwent HSCT for PID at a median age of 12 months (range, 1 to 220 months) with a median follow up of 14.4 months. Infants accounted for 51.3% of the cohort and the male female ratio was 3:1. SCID (25%) and HLH (25%) were the more frequent diagnoses. Matched family donor was available in 36.4% and 44.3% children had a haploidentical HSCT. Reduced and myeloablative conditioning regimens were used with 64% children receiving a treosulfan based conditioning regimen. Peripheral blood stem cells were the predominant graft source at 69.3%. The survival in infants (60.2%) was inferior to children aged over 1 year (75.7% p value = 0.01). Children with Wiskott Aldrich syndrome (74.3%) and chronic granulomatous disease (82.6%) had the best outcomes. The survival was superior in children receiving HSCT from a matched sibling (78%) versus an alternate donor HSCT (61% p value = 0.04). In the cohort transplanted after January 2016 survival improved from 26.8% to 77.5% (p value = 0.00). Infection remains the main cause of mortality at in over 50% children. The 5-year overall survival rate was 68%. Conclusion: Survival of children with PID undergoing HSCT in India has improved dramatically in last 5 years. Alternate donor HSCT is now feasible and has made a therapeutic option accessible to all children with PID.

Casein Kinase II (CK2) as a Therapeutic Target for Hematological Malignancies.

BACKGROUND: Casein kinase II (CK2) is a pro-oncogenic protein, which is emerging as a promising therapeutic target in cancer. Recent studies have revealed an important role for CK2 in tumorigenesis. High levels of CK2 are noted in many malignancies including leukemia. Use of CK2 inhibitors in various malignancies including breast, prostate, and lung cancer are being tested. Although many CK2 inhibitors exist, only a few have emerged as selective inhibitors that are potent and effective. CX-4945 is a selective, orallybioavailable small molecule inhibitor, which has shown encouraging results in pre-clinical models of leukemia. METHODS: In this review we will elaborate on the structure and physiological function of the CK2 protein as well as its role in cancer. We will review, in depth, the role of CK2 in leukemia and its mechanisms of tumorigenesis via phosphorylation of the tumor suppressor protein Ikaros. We will discuss both the importance of Ikaros in leukemia suppression and the restoration of Ikaros' tumor suppressor function after CK2 inhibition by CX-4945 (a CK2-specific inhibitor). RESULTS: CK2 is an oncogene that is overexpressed in hematological malignancies. In high risk Pre-B ALL, CK2 phosphorylates Ikaros tumor suppressor and promotes leukemogenesis. Inhibition of CK2 using CX4945 restores Ikaros function and leads to anti leukemic effects in vitro and in pre-clinical leukemia models. CONCLUSION: CK2 is an attractive target in treatment of various cancers. Currently only a few specific CK2 inhibitors are available. Preclinical studies using CK2 inhibitor, CX4945 in high risk pediatric leukemias have shown promising results and warrants further testing in other types of leukemia.

Potassium changes associated with blood transfusion in pediatric patients.

Storing packed red blood cells (pRBCs) increases the potassium concentration. This effect is characterized in citrate phosphate dextrose/citrate phosphate dextrose adenine units but not published for Adsol (AS-5) units. The change in whole-blood potassium concentration in pediatric patients during routine transfusion is also poorly characterized. In this study, pediatric patients undergoing transfusion had pre- and posttransfusion whole-blood potassium measurements. The pRBC unit transfused and the unit's segment were sampled, with potassium concentration measured. In addition, potassium concentration in AS-5 units was measured over 42 days of storage. Unit extracellular potassium increased in AS-5 units after day 7 at 0.83 mmol/L/d. The mean change in patient potassium concentration was 0.08 mmol/L (range, -0.5 to 0.5 mmol/L). No correlation with unit age or unit potassium concentration was identified with change in patient whole-blood potassium concentration. The lack of clinical effect on patient potassium does not support the use of "fresh" pRBC units with routine pediatric transfusion.