Seasonal Human Coronavirus Respiratory Tract Infection in Recipients of Allogeneic Hematopoietic Stem Cell Transplantation.

BACKGROUND: Little is known about characteristics of seasonal human coronaviruses (HCoVs) (NL63, 229E, OC43, and HKU1) after allogeneic stem cell transplantation (allo-HSCT). METHODS: This was a collaborative Spanish and European bone marrow transplantation retrospective multicenter study, which included allo-HSCT recipients (adults and children) with upper respiratory tract disease (URTD) and/or lower respiratory tract disease (LRTD) caused by seasonal HCoV diagnosed through multiplex polymerase chain reaction assays from January 2012 to January 2019. RESULTS: We included 402 allo-HSCT recipients who developed 449 HCoV URTD/LRTD episodes. Median age of recipients was 46 years (range, 0.3-73.8 years). HCoV episodes were diagnosed at a median of 222 days after transplantation. The most common HCoV subtype was OC43 (n = 170 [38%]). LRTD involvement occurred in 121 episodes (27%). HCoV infection frequently required hospitalization (18%), oxygen administration (13%), and intensive care unit (ICU) admission (3%). Three-month overall mortality after HCoV detection was 7% in the whole cohort and 16% in those with LRTD. We identified 3 conditions associated with higher mortality in recipients with LRTD: absolute lymphocyte count <0.1 × 109/mL, corticosteroid use, and ICU admission (hazard ratios: 10.8, 4.68, and 8.22, respectively; P < .01). CONCLUSIONS: Seasonal HCoV after allo-HSCT may involve LRTD in many instances, leading to a significant morbidity.

Clinical course of myeloproliferative leukaemia virus oncogene (MPL) mutation-associated familial thrombocytosis: a review of 64 paediatric and adult patients.

Familial thrombocytosis (FT) is a rare hereditary haematological disorder characterised by increased platelet count, usually caused by germ-line mutations in thrombopoietin (THPO), myeloproliferative leukaemia virus oncogene (MPL) or Janus kinase 2 (JAK2) genes, and can be associated with increased risk of thrombosis. We aimed to determine the yield of diagnostic tests, assess treatment received and describe the clinical course of MPL-associated FT. We retrospectively reviewed all paediatric and adult haematology patients diagnosed with MPL-related FT, who were seen in our clinics from March 2013 to February 2021. Of 64 eligible patients, 26 (41%) were aged <14 years, while the remaining 38 (59%) patients were adults. The median (interquartile range) age at diagnosis was 20 (33·5) years. In all, 26 tribes were represented in this cohort of 64 patients, out of which 31 (48%) patients belonged to two tribes. A total of 60 patients (94%) had thrombocytosis on blood count. Additional genetic tests, including myelodysplastic syndrome (MDS) gene panel, Philadelphia gene breakpoint cluster region-Abelson (BCR-ABL) and JAK2, were carried out for 52 patients and only one patient was positive for JAK2 mutation. In all, 21 (33%) patients were prescribed aspirin and seven (11%) were prescribed hydroxyurea. Overall, 63 (98%) patients did not develop any thrombotic or haemorrhagic event. There was no significant association of MPL-mutated FT with thrombosis or haemorrhage.

Hematological indices in the adult saudi population: Reference intervals by gender, age, and region.

Introduction: Hematological parameters are critical in disease diagnosis, management, and monitoring; however, complete blood count (CBC) reference intervals vary across populations. The aim of the current study was to provide the reference ranges of hematological parameters/indices in the healthy adult Saudi population. Methods: A multicenter retrospective cross-sectional study was conducted with a sample of employees who were screened pre-employment from January 2015 to December 2019, at tertiary care hospitals in three regions. Demographic and CBC data were extracted from the electronic health system. The 2.5th and 97.5th percentiles were used to determine the reference intervals. Results: Of a total of 1,388 participants, 53.82% were male. The majority 96% was less than 40 years old, and 85% were from the Central region. Gender-related differences were observed for the RBC count, Hb, HCT, MCV, MCH, MCHC, and the platelet count. Age-related differences were observed for the RBC, Hb, HCT, and eosinophils. The WBC parameters did not differ by gender or age categories. Region-related differences were observed for the RBC, hemoglobin, HCT, MCV, WBC, and basophils. The platelet count was higher in the female group, the age group 40 years and above, and in the Western region. The prevalence of anemia was high in the female group and the Eastern region. The overall neutropenia rate was 12.8%. Conclusion: The data from this study provide hematological parameter reference ranges for the adult Saudi population by gender, age, and region. Gender and age-related differences were observed for the hematological parameters. Anemia was more frequent in the female group and the Eastern region. Caution must be taken when comparing or interpreting results from different age groups, gender, region of origin, and ethnicity.

Outcome of haploidentical versus matched sibling donors in hematopoietic stem cell transplantation for adult patients with acute lymphoblastic leukemia: a study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation.

BACKGROUND: Non-T-cell depleted haploidentical hematopoietic stem cell transplantation (HaploSCT) is being increasingly used in acute lymphoblastic leukemia (ALL) with improving patient outcomes. We have recently reported that outcomes of adult patients (pts) with ALL in complete remission (CR) receiving HaploSCT are comparable to unrelated donor transplants. We now compared HaploSCT and matched sibling donor (MSD) transplants in pts with ALL. AIM: To assess transplantation outcomes of HaploSCT and MSD transplants in pts with ALL in CR. METHODS: We retrospectively analyzed adult patients (≥ 18 years) with ALL who underwent their first allogeneic stem cell transplantation (alloSCT) in first or second CR between 2012 and 2018, either from a T cell replete Haplo or MSD donor, and whose data were reported to the Acute Leukemia Working Party (ALWP) of the European Society for Blood and Marrow Transplantation (EBMT). Multivariate analysis (MVA) adjusting for differences between the groups was performed using the Cox proportional hazards regression model. Propensity score matching was also performed to reduce confounding effects. RESULTS: The analysis comprised 2304 patients: HaploSCT-413; MSD-1891. Median follow-up was 25 months. Median age was 37 (range 18-75) and 38 (18-76) years in HaploSCT and MSD, respectively. HaploSCT patients were transplanted more recently than those transplanted from MSD (2016 vs 2015, p < 0.0001). A higher rate of HaploSCT was in CR2 (33.4% vs 16.7%, p < 0.0001), respectively, and fewer received myeloablative conditioning (68% vs 83.2%, p < 0.0001). Cytomegalovirus (CMV) seropositivity was lower in HaploSCT patients (22% vs 28%, p = 0.01) and donors (27.1% vs 33%, p < 0.02), and a higher proportion of the HaploSCTs were performed using a bone marrow (BM) graft (46.2% vs 18.6%, p < 0.0001). The 2 groups did not differ with regard to gender, Karnofsky performance status score, ALL phenotype, Philadelphia chromosome (Ph) positivity and pre-alloSCT measurable residual disease (MRD). Graft versus host disease (GVHD) prophylaxis was mainly post-transplant cyclophosphamide (PTCy) based (92.7%) in the HaploSCT setting, while it was mostly pharmacologic in the setting of MSD (18.7% received ATG). Cumulative incidence of engraftment at day 60 was higher in MSD transplants compared to HaploSCT (98.7% vs 96.3%, p = 0.001), respectively. Day 180 incidence of acute (a) GVHD II-IV and III-IV was higher in HaploSCT vs. MSD: 36.3% vs 28.9% (p = 0.002 and 15.2% vs 10.5% (p = 0.005), respectively. Conversely, the 2-year chronic (c) GVHD and extensive cGVHD were 32% vs 38.8% (p = 0.009) and 11.9% vs 19.5% (p = 0.001) in HaploSCT vs MSD, respectively. Main causes of death were leukemia (31.8% vs 45%), infection (33.1% vs 19.7%) and GVHD (16.6% vs 19.7%) for HaploSCT and MSD, respectively. Two-year relapse incidence (RI), non-relapse mortality (NRM), leukemia-free survival (LFS), overall survival (OS) and GVHD-free, relapse-free survival (GRFS) were 26% vs 31.6%, 22.9% vs 13%, 51% vs 55.4%, 58.8% vs 67.4% and 40.6% vs 39% for HaploSCT and MSD, respectively. In the MVA, RI was significantly lower in HaploSCT in comparison with MSD, hazard ratio (HR) = 0.66 (95% CI 0.52-0.83, p = 0.004), while NRM was significantly higher, HR = 1.9 (95% CI 1.43-2.53, p < 0.0001). aGVHD grade II-IV and grade III-IV were higher in HaploSCT than in MSD HR = 1.53 (95% CI 1.23-1.9, p = 0.0002) and HR = 1.54 (95% CI 1.1-2.15, p = 0.011), respectively. Extensive cGVHD was lower in HaploSCT compared with MSD, HR = 0.61 (95% CI 0.43-0.88, p = 0.007), while total cGVHD did not differ significantly, HR = 0.94 (95% CI 0.74-1.18, p = 0.58). LFS, OS and GRFS did not differ significantly between the 2 transplant groups, HR = 0.96 (95% CI 0.81-1.14, p = 0.66); HR = 1.18 (95% CI 0.96-1.43, p = 0.11) and HR = 0.93 (95% CI 0.79-1.09, p = 0.37), respectively. These results were confirmed in a matched-pair analysis. CONCLUSIONS: Outcomes of adult patients with ALL in CR receiving alloSCT from haploidentical donors are not significantly different from those receiving transplants from MSD in terms of LFS, OS and GRFS.

Optimal pre-emptive cytomegalovirus therapy threshold in a patient population with high prevalence of seropositive status.

INTRODUCTION: Preemptive therapy (PET) for cytomegalovirus (CMV) reactivation post allogeneic hematopoietic stem cell transplantation (SCT) was shown to decrease the incidence of CMV disease. However, the optimal PET threshold is elusive. PURPOSE OF THE STUDY: To examine the efficacy of PET initiation at a viral threshold of 1000 copies/mL (1560 IU/mL) in a patient population with high prevalence of CMV seropositive status. PATIENTS AND METHODS: A single center retrospective review of patients that underwent allogeneic SCT was done. RESULTS: A total of 195 allogeneic SCT recipients were included with median follow up of 18.1 (0.7-95.6) months. A total of 178 (91 %) of patients had a positive CMV PCR with median days to initial reactivation post SCT of 17 (1-1187); 129 patients had peak CMV titer < 1000 copies/mL (low titer) whereas the remaining 49 patients had a peak titer ≥ 1000 copies/mL (high titer). 120 (93 %) of patients with low titers cleared spontaneously with median time to clearance of 40 days (4-188). One patient in the high titer group developed CMV disease. At multivariable analysis; age at SCT HR 1.02 (1.004-1.04; 0.017), malignant vs. benign condition HR 9.4 (2.47-61; 0.0005) and cGVHD HR 0.37 (0.2-0.65; 0.0005) were significant for OS. CONCLUSIONS: CMV reactivation post SCT was very common in patients with high prevalence of seropositive status. A PET threshold of 1000 copies/mL (1560 IU/mL) appears desirable as it was associated with spontaneous clearance in over 90 % of patients while minimizing treatment related toxicity. Validation of these observations is warranted.

Interim Functional Imaging Is an Independent Predictor of Progression-free Survival in Advanced Classical Hodgkin Lymphoma - A Real-world Analysis.

BACKGROUND: Response-adapted therapy in advanced classical Hodgkin lymphoma (cHL) using interim functional imaging (IFI) is under active investigation. PATIENTS AND METHODS: We retrospectively examined patients with advanced cHL receiving 2 front-line regimens stratified by IFI results at our institution. Time to endpoint analysis was estimated using the method of Kaplan-Meier with log ranks. Cox regression modeling was computed for multivariable analysis. RESULTS: A total of 124 patients with advanced cHL with a median follow up of 40.9 months were included. A total of 84 (67.7%) received ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine), whereas the remaining 40 (32.3%) received ABVD/eBEACOPP (escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone). A positive IFI was seen in 36 (29%) patients. The corresponding 3-year progression free survival (PFS) stratified by IFI was 81.7% (95% confidence interval [CI], 70.1%-88.8%) versus 48.3% (95% CI, 30.4%-64.1%) (P < .0001) for patients with negative or positive scan, respectively. Escalation to eBEACOPP from ABVD following a positive IFI resulted in a significantly higher 3-year PFS at 58.7% (95% CI, 0.3-0.79) versus 39.7% (95% CI, 0.18-0.61) respectively (P = .00015). Overall survival (OS) was similar across the groups (P = .44) irrespective of therapy received. At multivariable analysis, IFI was the only predictor of PFS with a hazard ratio of 4.6 (95% CI, 1.9-10.8; P = .0008) whereas therapy escalation had a hazard ratio of 0.66 (95% CI, 0.14-3.4; P = .62). CONCLUSION: IFI is an independent predictor of PFS in advanced cHL and can guide therapeutic decisions in the real world. Given the inferior outcome seen in patients with a positive IFI, novel approaches of therapy are warranted.

HLA-A, B, C, DRB1 and DQB1 allele and haplotype frequencies in volunteer bone marrow donors from Eastern Region of Saudi Arabia.

We analyzed HLA allele and haplotype frequencies from donors from the Eastern region of Saudi Arabia. A cross-sectional study was performed on 2405 bone marrow donors from the Eastern region. HLA typing was carried out by sequencing. The most common HLA allele groups were HLA-A*02:01:01G (11.08%), A*01:01:01G (10.40%), HLA-B*52:01:01G (8.79%), B*18:01:01G (8.07%), HLA-C*04:01:01G (17.88%), C*12:03:01G (10.23%), HLA-DRB1*10:01 (14.89%), DRB1*03:01:01G (14.10%), HLA-DQB1*02:01:01G (24.53%) and DQB1*05:01:01G (20.17%). The most frequent HLA-A~ C~ B~ DRB1~ DQB1 haplotypes were HLA-A*01:03~ C*15:05:01G~ B*73:01~ DRB1*10:01:01~ DQB1*05:01:01G (3.11%) and HLA-A*01:01:01G~ C*12:02:01G~ B*52:01:01G~ DRB1*15:02:01~ DQB1*06:01:01G (2.25%). When comparing the allele and haplotype frequencies of the Eastern regions' population to those from the Central region we found significant differences in several allele frequencies including A*01:01:01G (P ≤ 0.0001), B*52:01:01G (P ≤ 0.0001), B*18:01:01G (P = 0.0001), C*12:03:01G (P < 0.0001), DRB1*10:01:01 (P < 0.0001) and DQB1*05:01:01G (P < 0.0001). Our data confirms genetic heterogeneity among the Saudi population.

Graft vs host disease impacts overall survival post allogeneic hematopoietic stem cell transplantation for acute lymphoblastic leukemia/lymphoma.

AIM: To examine the outcome and prognostic factors for high risk patients with acute lymphoblastic leukemia/lymphoma (ALL/LBL) who underwent allogeneic hematopoietic stem cell transplantation (HCT) at our center during the period of 2010-2017. METHODS: After due institutional review board approval, patients with high risk ALL/LBL post HCT were identified and included. All records were retrospectively collected. Time to event analysis was calculated from the date of HCT until event of interest or last follow up with Kaplan-Meir means. Cox regression model was used for multivariable analysis calculation. RESULTS: A total of 69 patients were enrolled and examined with a median age of 21 (14-61). After a median follow up of 15 mo (2-87.3), the 2-year cumulative incidence of relapse, cumulative incidence of non-relapse mortality, progression free survival and overall survival (OS) were 34.1%, 10.9%, 54.9% and 62.8%, respectively. In a multivariable analysis for OS; acute graft vs host disease (GVHD) and chronic GVHD were significant with corresponding hazard ratio 4.9 (1.99-12; P = 0.0007) and 0.29 (0.1-0.67; P = 0.0044), respectively. CONCLUSION: Allogeneic-HCT for high risk ALL/LBL resulted in promising remissions particularly for patients with cGVHD.

Splenectomy vs. rituximab as a second-line therapy in immune thrombocytopenic purpura: a single center experience.

Immune thrombocytopenic purpura (ITP) is a common hematological disease treated primarily by corticosteroids. The aim of the present study was to compare response rate between patients, underwent splenectomy vs. rituximab as second-line therapy. Adult patients diagnosed with ITP who did not respond to corticosteroids or relapsed during the period 1990-2014 were included in a quasi-experimental study. Categorical variables were compared using Fisher exact test. Response to treatment was compared using logistic regression. Data were analyzed using SAS V9.2. One-hundred and forty-three patients with ITP were identified through medical records. Of 62 patients treated, 30 (48.38%) required second-line therapy. 19 (63%) patients received rituximab, and 11 (37%) underwent splenectomy. Platelets at diagnosis were not different between study groups (p = 0.062). Splenectomy group patients were younger (p = 0.011). Response to second-line therapy showed no significant difference between two groups (OR 2.03, 95% CI (0.21-22.09), p = 0.549). Results did not show a statistically significant difference in platelet counts over time between treatment groups (p = 0.101). When used exclusively as a second-line therapy for steroid-refractory ITP, the response rate was not statistically different between rituximab and splenectomy. However, further large studies are needed to assess the response rates for these treatment modalities as a second-line therapy.

Lymphocyte recovery is an independent predictor of relapse in allogeneic hematopoietic cell transplantation recipients for acute leukemia.

AIM: To examine the optimal absolute lymphocyte count (ALC) cut-off utilizing receiver operator characteristics (ROC) in addition to graft characteristics associated with early ALC recovery. METHODS: Patients who received T-cell replete peripheral hematopoietic cell transplantation (HCT) for acute leukemia were identified. ALC cut-off was established using ROC analysis and subsequently the cohort was stratified. Time to endpoint analysis and cox regression modelling was computed to analyze outcomes. RESULTS: A total of 72 patients met the inclusion criteria and were analyzed. Optimal ALC cut-off was established to be on day 14 (D14) with ALC > 0.3 × 109/L. At 2 years, cumulative incidence of relapse was 16.9% vs 46.9% (P = 0.025) for early and delayed lymphocyte recovery cohorts, respectively. Chronic graft vs host disease was more prevalent in the early lymphocyte recovery (ELR) group at 70% vs 27%, respectively (P = 0.0006). On multivariable analysis for relapse, ELR retained its prognostic significance with HR = 0.27 (0.05-0.94, P = 0.038). CONCLUSION: ELR is an independent predictor for relapse in patients receiving allogeneic HCT for acute leukemia. ELR was influenced by graft characteristics particularly CD34 count.

Clinical characteristics and genetic subtypes of Fanconi anemia in Saudi patients.

We reviewed our institutional experience from 2011 to 2015 on new cases of Fanconi anemia (FA). Ten unrelated cases were diagnosed during this period. Four patients with severe aplastic anemia (SAA) had c.2392C > T (p.Arg798*) BRIP1/FANCJ mutation. Another child with SAA had novel c.1475T > C (p.Leu492Pro) FANCC mutation. One individual with SAA and acute myeloid leukemia had c.637_643del (p.Tyr213Lysfs*6) FANCG mutation. Three patients presented with early onset of cancer, two had BRCA2 mutation c.7007G > A (p.Arg2336His) and one had a novel c.3425del (p.Leu1142Tyrfs*21) PALB2 mutation. Another infant with c.3425del PALB2 mutation had clonal aberration with partial trisomy of the long arm of chromosome 17. Mutations in FA downstream pathway genes are more frequent in our series than expected. Our preliminary observation will be confirmed in a large multi-institutional study.