Hemopoietic Stem Cell Transplantation Research Articles

Late Adverse Effects after Treatment for Childhood Acute Leukemia

The aim of this review is to raise awareness and knowledge among healthcare professionals and policymakers about late adverse effects in survivors of childhood leukemia. With contemporary treatment, over 90% of children with acute lymphoblastic leukemia (ALL) and over 60% with acute myeloid leukemia (AML) are cured. Large cohort studies demonstrate that 20% of ALL and most AML survivors have at least one chronic health condition by 20-25 years after diagnosis. These are life-changing or threatening in some survivors and contribute to increased premature mortality. We describe the frequency, causes, clinical features, and natural history of the most frequent and severe late adverse effects in childhood leukemia survivors, including subsequent malignant neoplasms, metabolic toxicity, gonadotoxicity and impaired fertility, endocrinopathy and growth disturbances, bone toxicity, central and peripheral neurotoxicity, cardiotoxicity, psychosocial late effects, accelerated ageing and late mortality. The wide range of late effects in survivors of haemopoietic stem cell transplant is highlighted. Recent developments informing the approach to long-term survivorship care are discussed, including electronic personalized patient-specific treatment summaries and care plans such as the Survivor Passport (SurPass), surveillance guidelines and models of care. The importance of ongoing vigilance is stressed given the increasing use of novel targeted drugs with limited experience of long-term outcomes. Conclusion. It is vital to raise awareness of the existence and severity of late effects of childhood leukemia therapy among parents, patients, health professionals, and policymakers. Structured long-term surveillance recommendations are necessary to standardize follow-up care.

COVID-19 outcomes in haemopoietic stem cell transplant recipients in Western Australia: the value of vaccination and antiviral therapy.

Coronavirus-19 (COVID-19) mortality rates among haemopoietic stem cell transplant (HSCT) patients are high, ranging between 20% and 40%. We prospectively evaluated the mortality outcomes of COVID-19 in Western Australian HSCT patients. A total of 32/492 (6.5%) HSCT recipients contracted COVID-19 during the study, of whom 30/32 (94%) developed mild or asymptomatic disease. Two allogeneic HSCT patients were hospitalised for severe COVID-19; one patient died. Stringent healthcare, social isolation practices, aggressive vaccination programmes and rapid access to COVID-19 antivirals may have promoted mild COVID-19 illness in Western Australian HSCT patients, resulting in one of the lowest COVID-19 mortality rates in HSCT recipients worldwide.

Reproductive medicine news. Digest of publications for 2023, issue 2

This issue of reproductive medicine news presents the second part of most relevant meta-analyses, reviews, prospective researches data, as well as innovative methods in the treatment of diseases of the reproductive system, presented in leading international periodicals in 2023. The briefly formulated list of topics contains such actual problems as: influence of active growing intramural myoma on IVF outcomes; birth rate after treatment of cancer and haemopoietic stem cell transplantation; chromosomal, gestational and neonatal outcomes of mosaic embryos with verified aneuploidy; artificial intelligence using in process of sperm selection for assisted reproductive technologies and personalized probiotic therapy of vaginal dysbiosis.

Mesenchymal stromal cells plus basiliximab improve the response of steroid-refractory acute graft-versus-host disease as a second-line therapy: a multicentre, randomized, controlled trial

BackgroundFor patients with steroid-refractory acute graft-versus-host disease (SR-aGVHD), effective second-line regimens are urgently needed. Mesenchymal stromal cells (MSCs) have been used as salvage regimens for SR-aGVHD in the past. However, clinical trials and an overall understanding of the molecular mechanisms of MSCs combined with basiliximab for SR-aGVHD are limited, especially in haploidentical haemopoietic stem cell transplantation (HID HSCT).MethodsThe primary endpoint of this multicentre, randomized, controlled trial was the 4-week complete response (CR) rate of SR-aGVHD. A total of 130 patients with SR-aGVHD were assigned in a 1:1 randomization schedule to the MSC group (receiving basiliximab plus MSCs) or control group (receiving basiliximab alone) (NCT04738981).ResultsMost enrolled patients (96.2%) received HID HSCT. The 4-week CR rate of SR-aGVHD in the MSC group was obviously better than that in the control group (83.1% vs. 55.4%, P = 0.001). However, for the overall response rates at week 4, the two groups were comparable. More patients in the control group used ≥ 6 doses of basiliximab (4.6% vs. 20%, P = 0.008). We collected blood samples from 19 consecutive patients and evaluated MSC-derived immunosuppressive cytokines, including HO1, GAL1, GAL9, TNFIA6, PGE2, PDL1, TGF-β and HGF. Compared to the levels before MSC infusion, the HO1 (P = 0.0072) and TGF-β (P = 0.0243) levels increased significantly 1 day after MSC infusion. At 7 days after MSC infusion, the levels of HO1, GAL1, TNFIA6 and TGF-β tended to increase; however, the differences were not statistically significant. Although the 52-week cumulative incidence of cGVHD in the MSC group was comparable to that in the control group, fewer patients in the MSC group developed cGVHD involving ≥3 organs (14.3% vs. 43.6%, P = 0.006). MSCs were well tolerated, no infusion-related adverse events (AEs) occurred and other AEs were also comparable between the two groups. However, patients with malignant haematological diseases in the MSC group had a higher 52-week disease-free survival rate than those in the control group (84.8% vs. 65.9%, P = 0.031).ConclusionsFor SR-aGVHD after allo-HSCT, especially HID HSCT, the combination of MSCs and basiliximab as the second-line therapy led to significantly better 4-week CR rates than basiliximab alone. The addition of MSCs not only did not increase toxicity but also provided a survival benefit.

Acute panmylelosis with myelofibrosis - A rare case report with review of literature.

Acute panmyelosis with myelofibrosis (APMF) corresponds to <1% cases of acute myeloid leukemia, which could be an underestimation due to missed diagnosis. Due to its rapidly fatal course, it warrants a timely and correct diagnosis. We present a case of a 44-year male who came with a short history of fever, generalised weakness, revealed pancytopenia with occasional circulating blast in the peripheral blood smear. Bone marrow aspirate was dry tap,biopsy revealed panmyelosis with myelofibrosis with increased (22%) blasts. Flowcytometric immunophenotyping, cytogenetics and molecular tests were undertaken. Together with clinical details, immunophenotypic profile, cytogenetics and molecular studies, the diagnosis of Acute panmyelosis with myelofibrosis was made and managed accordingly. 32 The WHO 2017 describes APMF as an acute panmyeloid proliferation with increased blasts (≥20% in the bone marrow or peripheral blood) and accompanying marrow fibrosis. APMF is rare with poor prognosis thus, must be differentiated especially from Acute megakaryoblastic leukemia to arrive at the correct diagnosis which will help reduce/prevent the early mortality by providing timely chemotherapy followed by upfront hemopoietic stem cell transplantation.

Detection of Bronchiolitis Obliterans Syndrome Using Nitrogen Multiple Breath Washout in Children Posthemopoietic Stem Cell Transplant

Bronchiolitis obliterans syndrome (BOS) is a severe complication following hemopoietic stem cell transplantation (HSCT) and is often undetected until there is significant deterioration in pulmonary function. Lung clearance index (LCI2.5) derived from the nitrogen multiple breath washout (N2MBW) test may be more feasible and sensitive than spirometry, which is currently used for surveillance and detection of BOS. We aimed to examine the feasibility of performing surveillance N2MBW in children post-HSCT, and in an exploratory analysis, determine if LCI2.5 led to earlier detection of BOS when compared to spirometric indices. Participants aged 5 to 17 years were recruited prior to receiving HSCT into a prospective, single-center, feasibility study at the Royal Children's Hospital, Melbourne. N2MBW and spirometry were performed within the month prior to transplant and repeated at 3, 6, 9, and 12 months post-transplant. Data were also collected on the presence of graft-versus-host (GVHD) disease in any organ, including the lungs. Twenty-one (12 male) children with a mean age of 13.4 (range 9.2 to 17.1) years at recruitment participated in this study. Prior to HSCT, all participants had normal LCI2.5, while 16 (76%) demonstrated normal forced expiratory volume in 1 second (FEV1). Ninety-nine percent of N2MBW tests were technically acceptable, compared with 66% of spirometry tests. Three participants developed BOS, while 2 participants died of other respiratory complications. At 6 and 12 months post-transplant, the BOS group had increases in LCI2.5 ranging from 3 to 5 units and mean reductions in FEV1 % predicted of 40% to 53% relative to pre HSCT values, respectively. In those who developed BOS, post-HSCT LCI2.5 values were significantly worse when compared with the no BOS group (P < .001). Relative changes in LCI2.5 and FEV1 were both predictive of BOS at 6 months post HSCT. This study demonstrates that N2MBW is a more feasible test compared with spirometry in children post HSCT. However, in an exploratory analysis, LCI2.5 did not lead to earlier detection of BOS, when compared to spirometry.

Venetoclax plus dose-adjusted R-EPOCH (VR-DA-EPOCH) or G-EPOCH bridging to subsequent cellular therapy for the patients with transformed lymphoma a single center clinical experience

Indolent lymphoma, including chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and follicular lymphoma (FL), can undergo histological transformation into an aggressive subtype, typically diffuse large B-cell lymphoma (DLBCL). The prognosis of transformed lymphoma is poor. In this study, we reported the efficacy and toxicity of a combination of venetoclax, dose-adjusted rituximab or obinutuzumab, etoposide, prednisone, vincristine, doxorubicin, and cyclophosphamide (VR-DA-EPOCH or VG-DA-EPOCH) in 11 patients with biopsy-proven histology transformation into DLBCL, including 8 patients with RT and 3 with transformed FL (tFL). The study was conducted between October 2019 and March 2023 at our single center. The median age of participants at enrolment was 53 years. Six patients (85.7%, 6/7) achieved complete remission (CR) at the end of treatment. The best overall response rate (ORR) and CR rate were both 72.7%, respectively. Two patients received autologous hemopoietic stem cell transplant (ASCT) while two patients received ASCT concurrently with CAR-T therapy for consolidation. With a median follow-up of 13.5 (range, 2.4–29.8) months after enrollment, the median event-free survival, progression-free survival, and overall survival were 9.4, 11.5, and 17.5 months, respectively. Hematologic toxicities of grade ≥3 consisted of neutropenia (90.9%, 10/11), thrombocytopenia (63.6%, 7/11), and febrile neutropenia (54.5%, 6/11). In conclusion, VR-DA-EPOCH or VG-DA-EPOCH was a promising strategy to achieve an early remission, bridging to cellular therapy within this population.

Guidelines for the diagnosis and management of adult aplastic anaemia: A British Society for Haematology Guideline.

Pancytopenia with hypocellular bone marrow is the hallmark of aplastic anaemia (AA) and the diagnosis is confirmed after careful evaluation, following exclusion of alternate diagnosis including hypoplastic myelodysplastic syndromes. Emerging use of molecular cyto-genomics is helpful in delineating immune mediated AA from inherited bone marrow failures (IBMF). Camitta criteria is used to assess disease severity, which along with age and availability of human leucocyte antigen compatible donor are determinants for therapeutic decisions. Supportive care with blood and platelet transfusion support, along with anti-microbial prophylaxis and prompt management of opportunistic infections remain key throughout the disease course. The standard first-line treatment for newly diagnosed acquired severe/very severe AA patients is horse anti-thymocyte globulin and ciclosporin-based immunosuppressive therapy (IST) with eltrombopag or allogeneic haemopoietic stem cell transplant (HSCT) from a matched sibling donor. Unrelated donor HSCT in adults should be considered after lack of response to IST, and up front for young adults with severe infections and a readily available matched unrelated donor. Management of IBMF, AA in pregnancy and in elderly require special attention. In view of the rarity of AA and complexity of management, appropriate discussion in multidisciplinary meetings and involvement of expert centres is strongly recommended to improve patient outcomes.

VEXAS syndrome: Clinical manifestations, diagnosis, and treatment.

VEXAS (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) syndrome is an adult-onset autoinflammatory syndrome characterized by somatic mutations in the UBA1 gene and is considered the prototype of hematoinflammatory diseases. Patients with VEXAS syndrome exhibit inflammatory and hematological manifestations that can lead to clinical diagnoses such as relapsing polychondritis, polyarteritis nodosa, Sweet syndrome, and myelodysplastic syndrome. Diagnosis requires bone marrow evaluation to identify cytoplasmic vacuoles in myeloid and erythroid precursors. However, genetic confirmation of mutations in UBA1 is necessary. Treatment is challenging and often involves glucocorticoids and immunosuppressants with variable responses. Hypomethylating agents and allogenic haemopoietic stem cell transplant are considered promising therapies. Prognosis is influenced by genetic and clinical factors. The aim of this review is to provide an overview of the pathogenesis, clinical presentation, treatment, and prognosis of VEXAS syndrome for the Latin American medical community.

Longitudinal Changes of Ocular Surface Microbiome in Patients Undergoing Hemopoietic Stem Cell Transplant (HSCT).

To evaluate changes in the ocular surface microbiome (OSM) between pre- and post-haemopoietic stem cell transplant (HSCT) in the same patient, and to assess the potential impact of these changes in ocular graft-versus-host disease (o)GVHD development. Lower fornix conjunctival swabs of 24 patients were obtained before and after HSCT and subjected to DNA extraction for amplification and sequencing of the V3-V4 regions of the bacterial 16S rRNA gene. The obtained reads were reconstructed, filtered, and clustered into zero-radius operational taxonomic units (zOTUs) at 97% identity level before taxonomic assignment, and biodiversity indexes were calculated. Transplant characteristics were recorded, and dry eye was diagnosed and staged 1-4 according to the Dry Eye WorkShop (DEWS) score. No significant difference in OSM alpha diversity between pre- and post-transplant was found. A significant difference in beta diversity was observed between patients with a DEWS score of 1 versus 3 (p = 0.035). Increased corneal damage between pre- and post-HSCT was significantly associated with a decrease in alpha diversity. The changes in OSM were not associated with oGVHD, nor with any transplant parameter. This preliminary study is the first study to analyse changes in the OSM before and after HSCT longitudinally. No trend in OSM biodiversity, microbial profile, or overall composition changes before and after HSCT was significant or associated with oGVHD onset. The great variability in the observed OSM profiles seems to suggest the absence of a patient-specific OSM "signature".

Tolerability in Transplant-Ineligible Patients with Newly Diagnosed Acute Myeloid Leukemia Treated with Venetoclax Based Combination Therapy: A Systematic Review and Meta-Analysis of Phase III Randomized Controlled Trials

Introduction Therapeutic challenge remains in older patients with acute myeloid leukemia (AML) with significant comorbidities who are not fit for induction chemotherapy and haemopoietic stem cell transplantation. Leukemic cells depend on BCL-2 protein (anti-apoptotic protein) for their survival. Venetoclax is a selective small-molecule BCL-2 inhibitor which binds to BCL-2 resulting in apoptosis of leukemic cells. In recent years, venetoclax has been approved in combination with azacitidine or low dose cytarabine in transplant-ineligible patients with newly diagnosed AML (ND AML). However, there are notable toxicities. The purpose of our meta-analysis is to determine tolerability, rates of treatment emergent serious adverse events (SAE), treatment discontinuation (TD) and treatment interruption (TI), dose reduction and 30-day mortality in transplant-ineligible patients with ND AML treated with venetoclax based combination therapy. Methods We systematically conducted a comprehensive literature search using MEDLINE, EMBASE databases and meeting abstracts from inception through June 30 th, 2023. Phase III RCTs utilizing venetoclax in transplant-ineligible patients with ND AML that mention tolerability, rate of treatment discontinuation and interruption, dose reduction, treatment emergent serious adverse events, 30-day mortality were incorporated in the analysis. Mantel-Haenszel (MH) method was used to calculate the estimated pooled risk ratio (RR) with 95% confidence interval (CI). Heterogeneity was assessed with Cochran's Q- statistic. Fixed effects model was applied. Results A total of 637 transplant-ineligible patients with ND AML from 2 phase III RCTs (VIALE-A and VIALE-V) were eligible. VIALE-A and VIALE-V compared azacitidine + venetoclax vs azacitidine + placebo, and venetoclax + low dose cytarabine vs placebo + low dose cytarabine respectively. The randomization ratio was 2:1 in both studies.TD due to treatment emergent adverse events (TEAE) was noted in 104 (24.5%) of venetoclax group vs 45 (21.2%) in control group with RR of 1.15 (95% CI: 0.85 -1.57; P = 0.37).TI due to TEAE was higher in the venetoclax group (68.9%) compared to control group (55.6%) with RR of 1.24 (95% CI: 1.08 -1.42; P = 0.002). 21 (4.9%) of patients in venetoclax group and 10 (4.7%) in the control group required dose reduction of treatment due to TEAE, RR 1.03 (95% CI: 0.50 -2.16; P = 0.93).Treatment emergent SAEs were reported in 77.4% in the venetoclax group vs 60% in control group (RR, 1.30; 95% CI: 1.15-1.46; P &amp;lt;0.0001). 30-day mortality was reported in 39 (9.1%) of patients in the venetoclax group and 20 (9.4%) in the control group with RR of 0.96 (95% CI: 0.58 -1.60; P = 0.89). Conclusions Our meta-analysis showed that there was no significant difference in the rate of treatment discontinuation and dose reduction due to adverse events in transplant-ineligible patients with ND AML treated with venetoclax combination regimens, compared to control arm although rates of treatment emergent SAEs and treatment interruption were considerably higher in the venetoclax-treated arm. However, the 30-day mortality rate was similar between the two groups. Longer follow up and timely supportive care are required to improve treatment emergent SAEs and treatment interruption.

Survival of Hodgkin Lymphoma Patients Treated with Novel Immunotherapies after Autologous Stem Cell Transplantation Failure: A Retrospective Analysis of the Italian Lymphoma Foundation (FIL)

Background: Classical Hodgkin lymphoma (HL) is considered a highly curable disease and nearly 80-90% of patients (pts) may achieve complete remission (CR) with standard chemotherapy (Engert et. al. NEJM 2010).However up to 30% of HL pts experience primary refractory disease or eventually relapse after first-line treatment (Barrington et. al. Blood 2016, Press O et al. Clin Oncol 2016). High-dose chemotherapy followed by autologous hemopoietic stem cell transplantation (autoHSCT) has been showed to be an active salvage treatment in approximately 50% pts with chemosensitive relapse. Before the advent of novel immunotherapies, the median survival duration for pts failing autoHSCT was only 10 months (Vose et. al. Blood 1992). In this setting the introduction of Brentuximab Vedotin (BV) (Younes et. al. JCO 2012) and of the checkpoint inhibitors (CPI) Nivolumab (nivo) (Herrera et. al. Blood 2018) or Pembrolizumab (Chen et.al. Blood 2019) have shown to significant therapeutic active. Aims: To assess the therapeutic effects of BV and CPI in prolonging PFS and OS in patients with HL r/r post autoHSCT. Methods: This is an observational, retrospective, multicentric study from 15 centers of the Fondazione Italiana Linfomi (FIL). Adult patients who received salvage treatment with BV or CPI for post autoHSCT r/r HL from January 2015 to June 2018 were included in the analysis; the times of observation was censored in December 2020. Patients that had received pre-autoHSCT BV or CPI, were excluded from the analysis. Results: 40 pts, 25 treated with BV and 15 with nivo were included into the study. Patients' main characteristics at diagnosis are summarize in Table 1. Overall response was achieved in 23 (56%) pts treated with BV and in 9 (60%) with nivo, respectively. 14 (35%) out of 40 responsive to BV (10 pts) or nivo (4 pts) received allogeneic hemopoietic stem cell transplantation (alloHSCT) consolidation. The median follow-up time from the time of autoHSCT failure of the entire cohort was 36 months (range 2-70). At last follow-up, 32 (80%) pts were in CR, 1 (2%) in PR, while 2 (5%) and 5 (13%) were in SD and PD, respectively. 34 (85%) pts were alive and 6 (15%) have died. In the entire cohort, the median PFS and OS from the time of autoHSCT failure was 36 months and not reached, respectively; the 36-months projected PFS and OS of 50% and 86%, respectively. The median PFS and the 36-months projected OS of pts who received or not received alloHSCT were superimposable (Figure 1). Conclusion: In this retrospective analysis of pts with HL failing autoHSCT, BV or nivo resulted very active therapeutic salvage therapies. The comparison with historical results of the pre BV/CPI era suggests a major significant improvement both in PFS and OS. A significant proportion of pts received post BV or nivo alloHSCT but the effect of this treatment in prolonging PFS and OS should be further evaluated.

Full CD34 Donor Chimerism Following CD34 Chimerism Directed Donor Lymphocyte Infusion Results in Reduced Relapse and Superior Overall Survival Compared with Mixed Chimerism Status in Allogeneic Haemopoietic Stem Cell Transplant Recipients

Introduction Peripheral blood CD34 donor chimerism (DC) is a clinically valuable method for detecting relapse of myeloid malignancies following allogeneic hematopoietic stem cell transplantation (alloHSCT). Our institution has recently shown that CD34 DC ≤80% was superior to CD3 DC for predicting relapse (1). While pre-emptive DLI has demonstrated efficacy in preventing relapse in the setting of falling whole unfractionated and CD3 DC, little has been reported about its utility in falling CD34 DC. Methods We conducted a retrospective analysis of consecutive patients who received DLI at the Alfred Hospital in Melbourne, Australia between January 2012 and January 2023. Peripheral blood CD34 DC was monitored in alloHSCT patients transplanted for myeloid malignancies or acute lymphoblastic leukaemia (ALL). CD34+ cells were enriched using magnetic beads and DC measured using an STR-PCR method, which had a sensitivity of 1%. DLI was administered to patients with CD34 ≤80% that did not respond to immunosuppression taper. DLI doses were based on donor type and recipient weight, with subsequent doses administered incrementally according to a predefined protocol. Starting doses were 3x10 6/kg for sibling donors, 1x10 6/kg for unrelated donors and 0.5x10 6/kg for haploidentical donors. DLI was discontinued upon achieving full DC (FDC) defined as CD34 DC &amp;gt; 95%, clinically significant graft-versus-host disease (GVHD), disease progression, or lack of available donor cells. Results One hundred and six patients received DLI between 2012 and 2023. Twenty-five of these patients received DLI for CD34 DC ≤80% without morphologic relapse. Eleven of 25 (44%) patients received DLI alone, while 14 (56%) patients received it in combination with other therapies, primarily a hypomethylating agent. At the time of DLI, 5 (20%) of the 25 patients had concurrent decreased CD3 DC ≤ 80%. The median follow-up period was 1.84 years (range 0.58 to 8.43 years). Sixteen of 25 (66.7%) patients achieved CD34 FDC while 8 (33.3%) had persistent CD34 mixed DC (CD34 MDC). One patient could not be assessed due to death from infection. Patient characteristics and outcomes according to response to DLI are presented in Table 1. The cumulative incidence of relapse was significantly lower in the CD34 FDC group (12.5% vs 75% at 2 years, p&amp;lt;0.001). Patients achieving CD34 FDC had improved progression-free survival (PFS) and overall survival (OS) compared to the CD34 MDC group (PFS median years not reached [95% CI 1.94-ND] vs 0.29 years [95% CI 0.09-ND], p&amp;lt;0.001; OS median years not reached vs 0.68 years [95% CI 0.58-ND], p=0.003; Figure 1). Rates of grade II-IV acute graft-versus-host-disease (aGVHD) post-DLI were 12.5% in those achieving FDC and MDC (Table 1). A significant proportion of patients (37.5%) achieving FDC developed moderate-severe cGVHD while the MDC group did not survive long enough to develop cGVHD (Table 1). The non-relapse mortality observed in the CD34 FDC group was 12.5% at 3 years post-DLI. Conclusion Our centre experience demonstrated that CD34-directed DLI reduced relapse risk and improved overall survival when FDC is restored in alloHSCT patients, with an acceptable toxicity profile. Only 20% of patients with CD34 MDC had concurrent CD3 MDC, highlighting the additional value of CD34 monitoring in guiding salvage DLI administration. In patients with CD34 MDC ≤80%, the target of DLI should be to achieve FDC (&amp;gt;95%) given the clear association with improved outcomes in this group. References 1/ Das TP, North D, Fleming SA, Tan JLC, Ivey A, Cummings NJ, Spencer A, Patil SS, Widjaja JML, Swain MI, Bourke C, O'Brien ME, Kliman DS, Curtis DJ. Peripheral Blood CD34 Donor Chimerism has Greater Clinical Utility Than CD3 for Detecting Relapse after Allogeneic Stem Cell Transplantation for Acute Myeloid Leukemia or Myelodysplastic Syndrome. Transplant Cell Ther. 2023 Jul;29(7):454.e1-454.e8. doi: 10.1016/j.jtct.2023.03.025.

Co-Occurrence of Familial Mediterranean Fever and Hematologic Malignancies: Case Report Series

Introduction: Familial Mediterranean Fever (FMF) is an autosomal recessive genetic disorder primarily found among individuals of Mediterranean descent, including Armenians, Italians, Greeks, Arabs, Turks and Jews. In the Armenian population, approximately 90% of FMF cases are associated with three main mutations (M694V, V726A, and M680I) in two alleles of MEFV gene, while more than 300 MEFV variants have been reported worldwide. The homozygous M694V genotype is associated with frequent renal failure due to amyloidosis. Clinical manifestations of FMF include periodic attacks of diffuse serositis with pain and fever that are treated with colchicine or biologic therapy. There is a scarcity of data on patients with FMF and hematologic malignancies. Limited data makes it difficult to generate evidence-based recommendations for the management of these patients, which is mostly based on expert opinions or few case reports. Here we report the case series of patients from Armenia with simultaneous presence of FMF and hematologic malignancies (FMFHM) and evaluate their management challenges. Methods: Data was collected from the Armenian National Registry of Blood Disorders, at the Hematology Center after Prof. R. Yeolyan, and through personal interviews conducted with each patient. Hematology Center is the only institution in Armenia managing hematologic malignancies. We have analyzed 8 patients diagnosed with both FMFHM during 2000-2020, treated in the pediatric (1 patient) and adult (7 patients) hematology departments. Results: 8 patients with FMFHM were identified, from which 4 were diagnosed with myeloproliferative neoplasms (MPN), 2 with acute leukemia (AL), and 2 with non-Hodgkin lymphoma (NHL). The median age of patients was 46, range 20-60 years. Only 5 (62.5%) of patients were regularly taking colchicine for FMF, while the rest refused it. Four MPN patients received treatment only with oral medications (tyrosine kinase inhibitors, hydroxyurea). Autologous hemopoietic stem cell transplantation (auto-HSCT) was performed in 1 NHL patient after indicated 1 st and 2 nd line immuno-chemotherapy. Another 2 AL patients and one NHL patient received protocol-based respective chemotherapy regimens. Moderate gastrointestinal (GI) complications (e.g., epigastric pain, nausea, vomiting, intestinal discomfort) was experienced by 7 (87.5%) patients. Allergic reactions (e.g., moderate skin rash, itching) were seen in 5 patient (62.5%), of which one developed severe anaphylactic shock. A patient with FMF and PMF had ischemic stroke caused by thrombi. Arterial hypertension occurred in 3 (37.5%). Only in one patient reduction of colchicine dosage was performed (1mg/day was reduced to 0.6mg/d), because of interaction with imatinib. The rest of patients received chemotherapy and colchicine treatment as indicated. All 8 patients are alive, 5 of them are in hematologic or molecular remission, two of which received concurrent colchicine treatment. One patient in remission developed renal failure due to FMF (colchicine was refused). Two patients with MPN treated with colchicine experienced disease stabilization. Conclusion: In conclusion, the concurrent appearance of FMFHM may potentially increase the risk of GI side effects, allergic complications, and arterial hypertension, however definitive conclusions require further investigations in larger patient cohorts. While the overall treatment responses were largely positive, the association between MEFV and HM mutations warrants deeper exploration to provide more precise drug administration recommendations for colchicine and cancer medications. Future studies in this area will contribute to a better understanding of the interplay between these conditions and guide optimal treatment strategies.

Drug Selection and Posology, Optimal Therapies and Risk/Benefit Assessment in Medicine: The Paradigm of Iron-Chelating Drugs

The design of clinical protocols and the selection of drugs with appropriate posology are critical parameters for therapeutic outcomes. Optimal therapeutic protocols could ideally be designed in all diseases including for millions of patients affected by excess iron deposition (EID) toxicity based on personalised medicine parameters, as well as many variations and limitations. EID is an adverse prognostic factor for all diseases and especially for millions of chronically red-blood-cell-transfused patients. Differences in iron chelation therapy posology cause disappointing results in neurodegenerative diseases at low doses, but lifesaving outcomes in thalassemia major (TM) when using higher doses. In particular, the transformation of TM from a fatal to a chronic disease has been achieved using effective doses of oral deferiprone (L1), which improved compliance and cleared excess toxic iron from the heart associated with increased mortality in TM. Furthermore, effective L1 and L1/deferoxamine combination posology resulted in the complete elimination of EID and the maintenance of normal iron store levels in TM. The selection of effective chelation protocols has been monitored by MRI T2* diagnosis for EID levels in different organs. Millions of other iron-loaded patients with sickle cell anemia, myelodysplasia and haemopoietic stem cell transplantation, or non-iron-loaded categories with EID in different organs could also benefit from such chelation therapy advances. Drawbacks of chelation therapy include drug toxicity in some patients and also the wide use of suboptimal chelation protocols, resulting in ineffective therapies. Drug metabolic effects, and interactions with other metals, drugs and dietary molecules also affected iron chelation therapy. Drug selection and the identification of effective or optimal dose protocols are essential for positive therapeutic outcomes in the use of chelating drugs in TM and other iron-loaded and non-iron-loaded conditions, as well as general iron toxicity.

Clinical Outcomes of Human Rhinovirus Infections in Pediatric Hemopoietic Stem Cell Transplant Patients

Abstract Background Respiratory viral infections (RVIs) are common among pediatric transplant patients, with Human rhinovirus (HRV) being most frequently. In pediatric patients undergoing hematopoietic cell transplant (HCT), HRV infection prior to, or early post-transplant has been associated with progression to lower respiratory tract infection (LRTI) and adverse outcomes. The primary objective is to describe the clinical presentation and outcomes of HRV infections in patients undergoing HCT at St. Jude Children’s Research Hospital. Methods This is a single-center retrospective cohort study. HCT recipients who had a respiratory sample positive for HRV (HRV positive) or negative for any respiratory virus (virus negative) between October 1, 2014, and December 31, 2017, were included. Testing was performed using BioFire® Respiratory Panel. Primary outcomes were progression to LRTI, ICU admission, all-cause mortality rate, and respiratory event-related mortality rate. Results A total of 227 patients (166 allogeneic and 61 autologous transplants) were included in the analysis. Of these, 108 (47.5%) were HRV positive and 119 (52.4%) were virus negative. Of the HRV patients, 63.6% were diagnosed pretransplant. All samples were nasopharyngeal, except for 1 tracheal aspirate. There were no significant differences in sex, race, type of transplant, underlying malignancy, and conditioning regimen between patients with and without HRV infection. However, patients who had HRV were significantly younger compared with virus negative (Table 1). Cough and rhinorrhea were more frequently observed in patients with HRV (53.7% vs 19.8%, and 60.2% vs 22.8%, respectively). Almost 1 in 4 patients with HRV had LRTI. No significant association was found between the severity of respiratory disease and the type of conditioning regimen, type of transplant, or absolute lymphocyte count (ALC) within a week of infection. HRV positive patients were more likely to be tested due to symptoms, have URTI, and present with co-infections compared to the virus negative group. There were no differences in the proportion of abnormal radiological findings, and no differences in outcomes between groups (Table 1). Clearance of HRV infection was confirmed with a negative PCR in 45 patients. Of these, 60% remained positive by week 4. Conclusion HRV infection is frequently detected in symptomatic patients undergoing transplant. Despite presenting respiratory symptoms more frequently, there was not a significant association with progression to LRTI, need for intensive care unit, mechanical ventilation or mortality.

47 Attention and Working Memory (WM) in Pediatric Patients Prior to Hemopoietic Stem Cell Transplant (HSCT) for Hematologic Malignancies

Objective:HSCT is increasingly used for curative therapy for patients with high risk hematologic diseases. Existing research regarding the neurocognitive impact of HSCT on pediatric patients is notably variable. One area of identified risk is attention/working memory (WM) [Perkins et al., 2007]. The current study examines the degree to which difficulties in attention/WM are present prior to HSCT, as assessed using parent-report of working memory and cognitive tests of attention span and working memory.Participants and Methods:Participants were 19 children and adolescents ages 6-17 years (M= 9.63, SD= 3.22) who were enrolled in a prospective longitudinal study monitoring neurocognitive outcomes in children undergoing HSCT. Participants were eligible for this study if they were 2-18 years old at the time of transplant and had a diagnosis that qualified for an allogenic HSCT. Participants were ineligible if they had a pre-HSCT developmental delay, were non-English speaking, and had a prior HSCT or prior CAR T-cell therapy. Participants were 53% female and 95% Caucasian. Diagnoses in the current study sample included acute lymphoblastic leukemia (n=10), acute myeloid leukemia (n=8), and myelodysplastic syndrome (n=1).Measures included were the Working Memory Index score from the Behavior Rating Inventory of Executive Function (BRIEF; Gioia et al., 2000) and the Digit Span subtest from the Wechsler Intelligence Scale for Children, Fourth Edition (WISC-IV; Wechsler, 2003) and the Wechsler Adult Intelligence Scale, Fourth Edition (WAIS-IV; Wechsler, 2008).Results:Mean scores on parent-reported WM scores and cognitive measures of attention/WM fell within normal limits, including the Digit Span Total score (M = 48.42, SD= 6.33), Digit Span Forward score (M = 47.28, SD = 9.9.83), and Digit Span Backward score (M = 48.94, SD = 6.31). However, further analyses suggested that between 11-32% of patients had scores falling at least one standard deviation below the mean on these measures, with more than half of the sample (52.6%) identified with at least one measured weakness in attention and WM. The most commonly identified weakness (33.3% of patients) was Digit Span Forward. Correlations between parent-reported WM issues and cognitive measures of attention and WM were generally strong, with parent report of WM significantly correlated with the Digit Span Total score (r(18)= -0.52, p=.02) and the Digit Span Forward score (r(18) = -0.51, p=.03). No correlations were found between Digit Span Backward and other measures of attention and WM.There were no significant differences in WM scores between patients with ALL and AML. Additional analyses will examine potential contribution of medical factors (e.g., pre-HSCT treatment) to pre-HSCT performance on measures of attention and WM.Conclusions:These results suggest that, prior to undergoing HSCT, pediatric patients present with attention and WM issues. This finding has implications for research related to neurocognitive outcomes in HSCT, indicating the need to obtain pre-HSCT cognitive data in this area in order to fully understand potential change after HSCT. In addition, providers may need to consider adapting communication methods with patients during their transplant stay, given potential attention and WM issues within this population.

The experiences of parents of children diagnosed with cerebral adrenoleukodystrophy.

Adrenoleukodystrophy (ALD) is a rare X-linked neurodegenerative disease, affecting the brain, spinal cord and adrenal cortex. Childhood cerebral ALD (CCALD) is the most severe form of disease, involving rapidly progressive neurological deterioration. The treatment option for CCALD is allogenic haemopoietic stem cell transplant, which is only successful for early-stage disease. Parents' experiences of CCALD can inform healthcare delivery. To detail the experiences of parents of children diagnosed with cerebral ALD. A descriptive qualitative study. Parents were recruited via a UK-based community support organisation. Data collection involved single semi-structured interviews structured around a topic guide and conducted remotely. Data were analysed using the thematic analysis approach. Twelve parents from 11 families with a total of 16 children with ALD contributed to the study. Their 16 children with ALD followed one of three disease pathways, determined by the extent of neurological damage at diagnosis. Three themes, and their respective sub themes, describe the pathways and what they meant for parents. 'No possibility of treatment' concerns situations when CCALD was diagnosed at an advanced stage, the landslide of deterioration parents witnessed and their efforts to maintain normality. 'Close to the treatment threshold' describes situations where a small treatment window required parents to make agonising treatment decisions. 'Watching and waiting' explains the challenges for parents when disease was detected early enabling children to benefit from timely treatment. Parents' experiences were largely defined by the extent of cerebral damage at diagnosis, which determined the availability and success of treatment. There were specific challenges related to the three situations, indicating areas where support from health and care services may help parents deal with this devastating diagnosis. This study indicates support needs of parents across the spectrum of CCALD diagnoses and highlights the critical importance of early diagnosis.

MRI graph parameters are longitudinal markers of neuronal integrity in multiple sclerosis

PurposeWe sought to determine if structural network parameters add to traditional markers of MS treatment response following immunoablation and autologous haemopoietic stem cell transplantation (IAHSCT). The post-IAHSCT paradigm afforded us the opportunity to study MS patients after relapsing biology had been effectively suppressed, enabling us to study the cortical substrate of progressive MS in a less confounded manner. MethodsIn this analysis of data from a phase 2 prospective study, associations between magnetic resonance graph parameters, N-acetylaspartate to creatine ratio (NAA/Cr), and serum neurofilament light chain (sNfL), amongst other markers, were assessed at 3 months pre-and 12 months post-IAHSCT. Correlations between graph parameter score changes and markers of brain health were calculated. Predictive factors of NAA/Cr or sNfL levels were calculated, adjusting for reference models. Model improvements were evaluated using the G2 likelihood-ratio test. Results24 patients (aged 18–38) were evaluated. Post-IAHSCT, high NAA/Cr and low sNfL (both measures of neuronal injury) were respectively associated with more favourable degree, density, clustering and path lengths, and degree, γ, and path length. Post-IAHSCT, absolute change in degree, path length and γ were associated with NAA/Cr and sNfL. Multivariate analysis demonstrated that the relative change in network parameters after IAHSCT accounted for 14% and 35% more variance in NAA/Cr and sNfL levels respectively than the reference model alone. ConclusionsCross-sectionally and longitudinally, network parameters demonstrate added utility as markers of disease severity in MS. These measures have the potential to capture cortical changes relevant to progressive non-relapsing biology in MS.

Q-HAM: a multicenter upfront randomized phase II trial of quizartinib and high-dose Ara-C plus mitoxantrone in relapsed/refractory AML with FLT3-ITD

BackgroundAbout 50% of older patients with acute myeloid leukemia (AML) fail to attain complete remission (CR) following cytarabine plus anthracycline-based induction therapy. Salvage chemotherapy regimens are based on high-dose cytarabine (HiDAC), which is frequently combined with mitoxantrone (HAM regimen). However, CR rates remain low, with less than one-third of the patients achieving a CR. FLT3-ITD has consistently been identified as an unfavorable molecular marker in both relapsed and refractory (r/r)-AML. One-quarter of patients who received midostaurin are refractory to induction therapy and relapse rate at 2 years exceeds 40%. The oral second-generation bis-aryl urea tyrosine kinase inhibitor quizartinib is a very selective FLT3 inhibitor, has a high capacity for sustained FLT3 inhibition, and has an acceptable toxicity profile.MethodsIn this multicenter, upfront randomized phase II trial, all patients receive quizartinib combined with HAM (cytarabine 3g/m2 bidaily day one to day three, mitoxantrone 10mg/m2 days two and three) during salvage therapy. Efficacy is assessed by comparison to historical controls based on the matched threshold crossing approach with achievement of CR, complete remission with incomplete hematologic recovery (CRi), or complete remission with partial recovery of peripheral blood counts (CRh) as primary endpoint. During consolidation therapy (chemotherapy and allogeneic hematopoietic cell transplantation), patients receive either prophylactic quizartinib therapy or measurable residual disease (MRD)-triggered preemptive continuation therapy with quizartinib according to up-front randomization.The matched threshold crossing approach is a novel study-design to enhance the classic single-arm trial design by including matched historical controls from previous clinical studies. It overcomes common disadvantages of single-armed and small randomized studies, since the expected outcome of the observed study population can be adjusted based on the matched controls with a comparable distribution of known prognostic and predictive factors. Furthermore, balanced treatment groups lead to stable statistical models. However, one of the limitations of our study is the inability to adjust for unobserved or unknown confounders.Addressing the primary endpoint, CR/CRi/CRh after salvage therapy, the maximal sample size of 80 patients is assessed generating a desirable power of the used adaptive design, assuming a logistic regression is performed at a one-sided significance level α=0.05, the aspired power is 0.8, and the number of matching partners per intervention patient is at least 1. After enrolling 20 patients, the trial sample size will be recalculated in an interim analysis based on a conditional power argument.ConclusionCurrently, there is no commonly accepted standard for salvage chemotherapy treatment. The objective of the salvage therapy is to reduce leukemic burden, achieve the best possible remission, and perform a hemopoietic stem-cell transplantation. Thus, in patients with FLT3-ITD mutation, the comparison of quizartinib with intensive salvage therapy versus chemotherapy alone appears as a logical consequence in terms of efficacy and safety.Ethics and disseminationEthical approval and approvals from the local and federal competent authorities were granted. Trial results will be reported via peer-reviewed journals and presented at conferences and scientific meetings.Trial registrationClinicalTrials.gov NCT03989713; EudraCT Number: 2018-002675-17.