Relationship between certain HLA alleles and the risk of cytomegalovirus reactivation following allogeneic hematopoietic stem cell transplantation.

INTRODUCTION: Evidence is emerging to support an association between certain human leukocyte antigen (HLA) alleles and the risk of cytomegalovirus (CMV) reactivation following allogeneic hematopoietic stem cell transplant (allo-HSCT). The primary aim of this study was to identify HLA alleles associated with resistance or susceptibility to CMV reactivation. METHODS: We studied 586 adults who underwent allo-HSCT for high-risk hematological malignancies. High-resolution HLA typing data were available for recipients and donors. HLA class I and II alleles observed at a frequency of >5% in our population were included in the analysis. A CMV viremia level of more than 200 IU/ml on weekly monitoring was considered to be indicative of CMV reactivation. RESULTS: The median follow-up time in surviving patients was 21 months (range 4-74 months). The cumulative incidence of CMV reactivation at 6 months in the entire cohort was 55% (95% confidence interval [CI] 50.8%-59.2%). Mismatched donors, increasing recipient age, occurrence of acute graft versus host disease and recipient CMV seropositivity were associated with an increased risk of CMV reactivation. HLA B*07:02 (hazard ratio 0.59, 95% CI 0.40-0.83) was associated with a decreased risk of CMV reactivation. Patients who developed CMV reactivation had a lower incidence of relapse, higher transplant-related mortality (TRM) and lower overall survival (OS) than those without CMV reactivation. There was an adverse correlation of OS and TRM with increasing numbers of CMV reactivations. CONCLUSION: We observed that HLA B*07:02 was associated with a decreased risk of CMV reactivation. CMV reactivation was associated with lower relapse post-transplant, but this did not translate into a survival benefit due to higher TRM.

Effect of pre-transplant JAK1/2 inhibitors and CD34 dose on transplant outcomes in myelofibrosis.

Allogeneic hematopoeitic cell transplantation (allo-HCT) is the only curative treatment for myelofibrosis (MF). We evaluate the impact of various factors on survival outcomes post-transplant in MF. Data of 89 consecutive MF patients (primary 47%) who underwent allo-HCT between 2005 and 2018 was evaluated. Fifty-four percent patients had received JAK1/2 inhibitors (JAKi) pre-HCT. The median CD34 count was 7.1x106 cells/kg. Graft failure was seen in 10% of the patients. Grade 3-4 acute GVHD (aGVHD) and moderate/severe chronic graft versus host disease (cGVHD) occurred in 24% and 40% patients, respectively. Two-year overall survival (OS) and relapse free survival (RFS) were 51% and 43%, respectively. Cumulative incidence of relapse (CIR) and non-relapse mortality (NRM) at 2 years were 11% and 46%, respectively. Higher CD34 cell dose (≤5 × 106 cells/kg vs 5-9 or ≥9 × 106  cells/kg) and lower pre-HCT ferritin (

Fresh vs. frozen allogeneic peripheral blood stem cell grafts: A successful timely option.

Cryopreservation of grafts has been established in autologous and cord blood transplantation, yet there is little experience regarding the effect of cryopreservation with sibling and unrelated grafts. We evaluated the effect of cryopreservation of grafts on allogeneic transplant outcomes using related, unrelated and haploidentical donors, including 958 patients, age 18-74 years (median 55) and using PBSC for various hematologic malignancies. Fresh grafts were received by 648 (68%) patients, 310 (32%) received cryopreserved. There was no difference between fresh vs cryopreserved grafts for neutrophil engraftment (P = .09), platelet engraftment (P = .11), graft failure (5.6% vs 6.8%, P = .46) and grade II-IV acute graft-vs-host disease (GVHD) (P = .71), moderate/severe chronic GVHD was observed in 176 (27%) vs 123 (40%) patients, respectively (P < .001). Multivariable analysis demonstrated no difference between fresh vs cryopreserved for OS (P = .39) and CIR (P = .08) while fresh grafts demonstrated borderline increased NRM (HR 1.27, 95% CI 1.02-1.59, P = .04). Of note, for patients with no or mild chronic GVHD, CIR was less for fresh compared to cryopreserved (HR = 0.67 for fresh, 95% CI 0.48-0.92, P = .01). We conclude there were no differences in engraftment and survival between fresh and cryopreserved grafts for allogeneic HCT, thus establishing cryopreservation to be a safe option for allogeneic HCT.

High incidence but low mortality of EBV-reactivation and PTLD after alloHCT using ATG and PTCy for GVHD prophylaxis.

We explore risk factors and impacts of post-transplant EBV-Reactivation (EBV-R) and PTLD in 270 patients that underwent RIC alloHCT using ATG-PTCy and cyclosporine for GVHD prophylaxis. Twenty-five (12%) patients had probable (n = 7) or proven (n = 18) PTLD. Patients were managed with reduction of immunosuppression and 22 with weekly rituximab (375 mg/m2 IV). ORR was 84%; 8 (32%) recipients died, and one-year OS and NRM of patients with PTLD was 59.7% and 37%, respectively. One hundred seventy-two (63.7%) recipients had EBV-R. One-year OS and RFS of patients with EBV-R were 68.2% and 60.6%, and of EBV-Negative patients were 62.1% and 50.1%, respectively. High incidence but low mortality of EBV-R and PTLD was documented. EBV-R induced a protective effect on RFS in multivariable analysis (HR 0.91, p = .011). Therefore, EBV-R may have a protective effect on RFS in this setting. Further research is necessary to evaluate the interplay of EBV-R, immune reconstitution, and post-transplant outcomes.

Dual T-cell depletion with ATG and PTCy for peripheral blood reduced intensity conditioning allo-HSCT results in very low rates of GVHD.

The efficacy of posttransplant cyclophosphamide (PTCy) and antithymocyte globulin (ATG) in controlling GVHD has been previously reported. We aim to study the safety and efficacy of the use of dual T-cell depletion with ATG and PTCy for peripheral blood reduced intensity conditioning regimen allo-HSCT in 270 patients with hematological malignancies. Median follow-up was 12.7 months. Nineteen percent of patients received grafts from a matched related donor, 46% from 10/10 matched unrelated donors (MUD), 16% from 9/10 MUD and 19% from haploidentical donors. Graft failure rate was 9%. CMV and EBV reactivation rates were 58 and 64%. The cumulative incidence of grade II-IV and III-IV acute GVHD at day + 100 was 20.1% and 4.6%, respectively. The CI of moderate/severe chronic GVHD at 1 year was 12.4%. There were no differences in the incidence of GVHD according to donor type. One-year OS, RFS, NRM, CIR, and GVHD-free/RFS respectively were 65.2%, 56.9%, 22.7%, 20.3%, and 47.6%. Higher disease-risk index and worse Karnofsky performance status were significant factors for poor outcomes. In conclusion, the use of T-cell dual depletion with ATG and PTCy results in very low rates of acute and chronic GVHD and acceptable relapse rates and NRM.

Impact of CD34+ cell dose on reduced intensity conditioning regimen haploidentical hematopoietic stem cell transplantation.

OBJECTIVES: Haploidentical hematopoietic stem cell transplant (haplo-SCT) has been associated with higher rates of graft rejection, and a higher dose of CD34+ cell dose is frequently requested. We aim to explore the impact of CD34+ cell dose in peripheral blood stem cell (PBSC) grafts using reduced intensity conditioning (RIC) in haplo-SCT. METHODS: Sixty-eight consecutive haplo-SCT in adult patients were included. Graft-vs-host disease (GVHD) prophylaxis consisted on ATG, PTCy, and CsA. The cohort was divided in two groups using CD34+ dose of ≥ 9 × 106 CD34+/Kg as cutoff point. Median follow-up was 8.9 months. RESULTS: Median cell dose infused was 9.32 × 106 CD34+/Kg. Forty (58.8%) recipients received grafts with CD34+ cells ≥9 × 106 /kg. The infusion ≥ 9 × 106 CD34+/Kg cell dose had a negative impact in overall survival (P = .03) after adjusting for age at transplant. The cumulative incidence of acute GVHD and graft failure were not significantly influenced per CD34+ cell dose. Only four recipients had grade III aGVHD, and all of them received grafts with a CD34+ cell dose ≥ 9 × 106 . CONCLUSION: In RIC haplo-SCT, recipients may not benefit from PBSC grafts with a CD34+/kg cell dose higher than 9 × 106 cells/kg, as it can have an adverse impact in post-transplant outcome.

Allogeneic stem cell transplant in myelodysplastic syndrome-factors impacting survival.

OBJECTIVES: The primary aim of this study was to evaluate survival outcomes following allo-HCT in myelodysplastic syndrome (MDS), and the secondary aim was to study variables impacting survival. METHODS: This analysis describes patient characteristics, treatment, and outcomes in 125 consecutive adult patients with MDS transplanted from 2005 to 2018. RESULTS: The median age was 61 years, and median follow-up in patients alive at last follow-up was 29 months. The 2-year OS and RFS were 39% (95%CI 30%-48%) and 35.3% (95% CI: 27%-44%), respectively. Transfusion dependence, high-risk cytogenetics, and high serum ferritin were independent risk factors for death. The cumulative incidence of relapse (CIR) and non-relapse mortality (NRM) at 2 years were 23% and 41.6%, respectively. High serum ferritin was significantly associated with NRM. There was no association between the percentage of bone marrow blasts (either at diagnosis or at pretransplant evaluation), on relapse or survival. Induction chemotherapy did not offer any survival advantage in MDS RAEB-2 patients compared to cytoreduction with azacytidine alone. CONCLUSION: Our results highlight the importance of karyotype on survival after allo-HCT and identify serum ferritin and transfusion dependence as important surrogate markers of outcome. In addition, our results demonstrate the efficacy of azacytidine for pretransplant cytoreduction.

Epstein-Barr virus associated post-transplant lymphoproliferative disorder mimicking acute graft versus host disease.

We present a case series of 3 patients to highlight the fact that PTLD post-transplant can mimic GVHD, and should be part of the differential diagnosis for diarrhea post allo-HCT. Awareness of this presentation has important therapeutic implications, as increased immune suppression for the management of GVHD, can worsen clinical features of PTLD. Diagnostic imaging and tissue biopsies should be undertaken early in post-transplant patients presenting with diarrhea or hepatic abnormalities, especially with atypical presentations like fever, and EBV PCR monitoring can expedite clinical decision-making in such complicated scenarios while awaiting results of gut biopsies.

Impact of central nervous system involvement in AML on outcomes after allotransplant and utility of pretransplant cerebrospinal fluid assessment.

OBJECTIVE: The primary objective was to assess the effect of central nervous system involvement in acute myeloid leukemia (CNS-AML) on outcomes after allogeneic hematopoietic stem cell transplant (allo-HCT). The secondary objective was to assess the utility of pretransplant cerebrospinal fluid (CSF) assessment in AML. METHODS: We retrospectively analyzed survival outcomes in 338 adult AML patients (with and without CNS-AML) after allo-HCT. CNS involvement was defined as clinical, pathological, or radiological evidence of CNS involvement any time after diagnosis. RESULTS: The median follow-up in surviving patients was 23.7 months. Twenty-five patients (7.4%) had prior history of CNS disease, with normal CSF pretransplant. Three patients had CSF blasts detected for the first time at pretransplant evaluation (0.88%). The 2-year OS and RFS in groups with and without CNS involvement were not significantly different. Patients with CNS-AML had significantly higher 1-year cumulative incidence of relapse (29.7% vs 16.9%, P = .048). Age more than 65 years and absence of marrow remission at transplant were significant adverse factors for survival. CONCLUSION: CNS-AML is not an independent risk factor for survival after allo-HCT, but can be associated with higher relapse rates. Pretransplant CSF assessment has low yield in detecting new CNS disease pretransplant in AML.

Reduced intensity allogeneic stem cell transplant with anti-thymocyte globulin and post-transplant cyclophosphamide in acute myeloid leukemia.

OBJECTIVES: We aimed to study the efficacy of reduced intensity conditioning (RIC) allo-HSCT combined with anti-thymocyte globulin (ATG) and post-transplant cyclophosphamide (PTCy) for graft-versus-host disease (GVHD) prophylaxis in AML. METHODS: One hundred forty-seven patients were included. All patients underwent unmanipulated peripheral blood stem cell RIC allo-HSCT. Median follow-up was 12.8 months (range 0.5-39). RESULTS: Median age was 58 years. Twenty-nine (20%) recipients received 10/10 MRD grafts, 69 (47%) 10/10 MUD grafts, 20 (13.6%) 9/10 MMUD, and 29 (20%) haploidentical grafts. The cumulative incidence of grade II-IV and III-IV acute GVHD at day +100, and moderate/severe chronic GVHD at 1-year were as follow: 14.3%, 1.4%, and 8.3%. There were no significant differences according to donor type (P = .46) and cumulative incidence of GVHD. One-year overall survival (OS), relapse-free survival (RFS), non-relapse mortality, and GVHD-free/Relapse-free survival were as follows: 66.9% (95% CI 58.4-74), 59.9%, and 18.7% and 53.7%. KPS ≤ 80 was predictive of worst OS (P = .04). Those recipients who received MUD transplants had better RFS (P = .01). CONCLUSIONS: RIC allo-HSCT combined with ATG and PTCy is safe and a potentially curative strategy and it is associated with impressive GRFS in AML.

Low rates of acute and chronic GVHD with ATG and PTCy in matched and mismatched unrelated donor peripheral blood stem cell transplants.

INTRODUCTION: We evaluated the combination of ATG and PTCy for GVHD prophylaxis in matched and mismatched unrelated PBSCTs for high-risk hematological malignancies. METHODS: We treated 102 patients with reduced intensity conditioning (RIC) with fludarabine, busulfan, and TBI 200 cGy. GVHD prophylaxis included rabbit ATG (thymoglobulin at total dose of 4.5 mg/kg divided over days -3 to -1), PTCy (50 mg/kg/day on day +3 and on day +4), and cyclosporine. Clinical and outcome data were collected retrospectively. RESULTS: Among 102 patients, 76 patients received 10/10 MUD transplants and 26 patients received 9/10 mismatched transplants. The median age was 59 years. At a median follow-up of 15 months (range 0.6 to -33 months), the 1-year OS in MUD and MMUD cohort was 75% and 50%, respectively (P = 0.027). The corresponding one-year PFS was 67% and 35%, respectively (P = 0.0024). The incidence of grade 3-4 acute GVHD was 11.8% in MUD and 3.8% in MMUD group, and that of NIH stage moderate/severe chronic GVHD in the 2 groups was 10.5% and 7.6%, respectively. Cytomegalovirus (CMV) reactivation was seen in 49% patients. The cumulative incidence of relapse was 21.1% in the MUD group and 42.3% in the MMUD group. CONCLUSION: Our experience shows that PTCy and ATG can be combined for GVHD prophylaxis in matched unrelated donor PBSCTs with low rates of Gr3-4 acute GVHD and chronic GVHD, and acceptable relapse rates.

Mediastinal Mass with Hyper-eosinophilia in a Young Boy -A Diagnostic Dilemma.

Mediastinal masses in children comprises of a heterogeneous group of tumours. In such cases, biopsy and histological analysis are mandatory for planning of treatment. We have reported an unusual aetiology for a mediastinal mass in a young boy presenting with features of Superior Vena Caval Obstruction (SVCO) who also had marked blood and marrow eosinophilia mimicking Chronic Eosinophilic Leukaemia (CEL). We have also discussed the differential diagnoses of mediastinal tumours with hyper-eosinophilia and possible therapeutic implications.

Hypercalcaemia with disseminated osteolytic lesions: a rare presentation of childhood acute lymphoblastic leukaemia.

Acute lymphoblastic leukaemia (ALL) presenting with hypercalcaemia and lytic bone lesions is a rare event in children unlike adults. We report a 15-year-old boy with acute lymphoblastic leukaemia and hypercalcaemia. He had normal peripheral blood count and the peripheral smear did not show blast. The bone marrow examination revealed Pre B ALL phenotype with aberrant expression of CD13. The skeletal survey showed osteolytic lesions. Hypercalcaemia was treated with zoledronic acid. He attained remission only after three lines of intensive chemotherapy protocols. He was planned for stem cell transplant. Meanwhile, he relapsed and died. A review of the literature also highlights characteristics similar to our case.

A Case Report of Concurrent IDH1 and NPM1 Mutations in a Novel t(X;2)(q28;p22) Translocation in Acute Myeloid Leukaemia without Maturation (AML-M1).

Acute myeloid leukaemia (AML) is one of the fatal haematological malignancies as a consequence of its genetic heterogeneity. At present, the prediction of the clinical response to treatment for AML is based not only on detection of cytogenetic aberrations but also by analysing certain molecular genetic alterations. There are limited in sights into the contribution, disease progression, treatment outcome, and characterisation with respect to the uncommon chromosomal abnormalities leading to AML. Here, we describe the clinical, morphological, cytogenetic, and mutational findings of a 52-year-old female patient with AML without maturation (AML-M1). Conventional karyotyping and spectral karyotyping (SKY) were done on metaphase chromosomes from bone marrow cells at the time of diagnosis. A mutation analysis was performed on the hotspot regions of various genes, including FLT3, CEBPA, NPM1, RAS, c-KIT, IDH1 and IDH2. Cytogenetic and mutation analyses revealed a novel translocation, t(X;2)(q28;p22), with both NPM1 and IDH1 mutations. To the best of our knowledge, the presence of both NPM1 and IDH1 mutations in t(X;2)(q28;p22) is a novel finding in AML.

A colonization of a different kind.

An unusual morphological pattern in the lymph node can at times, pose a diagnostic problem. We report a case of a 55 year old male whose cervical lymph node biopsy showed an unusual pattern of follicular colonization by T-lymphoblasts. The interfollicular area showed a diffuse infiltrate of Langerhans cells. A diagnosis of a T lymphoblastic lymphoma coexisting with Langerhans cell histiocytosis like lesion was made, keeping in mind lack of clinical evidence for the latter.

Visceral leishmaniasis with aplastic bonemarrow: coincidental or causal.

Acquired aplastic anaemia (AAA) is caused by aetiologies ranging from infectious agents, chemical toxins, drugs, and autoimmune disorders. Few reports exist which establish a causal association of parasites in AAA. Causal association of Leishmania donavani infection in AAA has not been reported to date.