Adenovirus infections occur in 5% to 21% of patients following stem cell transplantation (SCT), with an associated mortality of up to 50%. However, a lack of prospective studies has hampered further ...developments in the understanding and management of this infection in the posttransplantation setting. We prospectively studied the incidence and outcome of adenovirus infections after SCT using preemptive screening and a policy of reduction or withdrawal of immunosuppressive therapy if the virus was isolated. The incidence of adenovirus infection was 19.7% (15 of 76), and the virus was isolated exclusively in recipients of T-cell–depleted grafts. Patients receiving 50 or 100 mg alemtuzumab in vivo were at the greatest risk of adenovirus infection (45% probability) regardless of donor type, and this was related to the slower lymphocyte recovery. Six (40%) of the 15 adenovirus-infected patients developed adenovirus disease. Severe lymphocytopenia (less than 300/μL) at the time of first detection of adenovirus was a major risk factor for development of adenovirus disease (P = .001). In addition, failure to reduce immunosuppression (P = .04) and a positive result of adenovirus polymerase chain reaction (PCR) in blood at diagnosis (P = .01) were both associated with fatal adenovirus disease. On the basis of this study, we recommend active surveillance for adenovirus infection in T-cell–depleted SCT and withdrawal or reduction of immunosuppressive treatment, if possible, in patients with adenovirus infection. Preemptive antiviral therapy is warranted for patients with severe lymphocytopenia or positive blood PCR, and in those in whom immunosuppressive therapy cannot be reduced.
Mycobacterium-
(Mw) was shown to boost adaptive natural killer (ANK) cells and protect against COVID-19 during the first wave of the pandemic. As a follow-up of the trial, 50 healthcare workers (HCW) ...who had received Mw in September 2020 and subsequently received at least one dose of ChAdOx1 nCoV-19 vaccine (Mw + ChAdOx1 group) were monitored for symptomatic COVID-19 during a major outbreak with the delta variant of SARS-CoV-2 (April-June 2021), along with 201 HCW receiving both doses of the vaccine without Mw (ChAdOx1 group). Despite 48% having received just a single dose of the vaccine in the Mw + ChAdOx1 group, only two had mild COVID-19, compared to 36 infections in the ChAdOx1 group (HR-0.46,
= 0.009). Transcriptomic studies revealed an enhanced adaptive NK cell-dependent ADCC in the Mw + ChAdOx1 group, along with downregulation of the TLR2-MYD88 pathway and concomitant attenuation of downstream inflammatory pathways. This might have resulted in robust protection during the pandemic with the delta variant.
Nonmyeloablative conditioning is increasingly used for transplantation in a wide range of diseases, but little is known about its impact on the incidence of infections and immune reconstitution. We ...examined the pattern and outcome of cytomegalovirus (CMV) infections monitored by polymerase chain reaction–based assays and treated preemptively in 101 patients following nonmyeloablative conditioning containing in vivo Campath-1H. Fifty-one patients (50%) had a CMV infection at a median of 27 days after transplantation with a probability of 84.8% in patients at risk of CMV infection. The probability of recurrence of CMV infection before and after 100 days was 53.6% and 46.6%, respectively, and was more common in unrelated donor transplant recipients. All 3 patients who developed CMV disease died of this complication. The 2 patients with late CMV disease had grade III to IV graft-versus-host-disease (GVHD), which occurred de novo in only 4% of patients and in another 10% following donor lymphocyte infusions. The median time to CD4+ T-cell count more than 200/μL was 9 months in the 48 patients studied. The probabilities of overall survival and nonrelapse mortality at 18 months were 65% and 27.8%, respectively, with no significant difference in survival between CMV-infected and -uninfected patients. The use of Campath-1H appeared to be associated with a low incidence of GVHD but a high incidence of CMV infections and prolonged immune paresis.
Allogeneic hematopoietic stem cell transplantation (HSCT) remains a curative option for children with high risk and advanced acute leukemia. Yet availability of matched family donor limits its use ...and although matched unrelated donor or mismatched umbilical cord blood (UCB) are viable options, they fail to meet the global need. Haploidentical family donor is almost universally available and is emerging as the alternate donor of choice in adult patients. However, the same is not true in the case of children. The studies of haploidentical HSCT in children are largely limited to T cell depleted grafts with not so encouraging results in advanced leukemia. At the same time, emerging data from UCBT are challenging the existing paradigm of less stringent HLA match requirements as perceived in the past. The use of posttransplantation cyclophosphamide (PTCY) has yielded encouraging results in adults, but data in children is sorely lacking. Our experience of using PTCY based haploidentical HSCT in children shows inadequacy of this approach in younger children compared to excellent outcome in older children. In this context, we discuss the current status of haploidentical HSCT in children with acute leukemia in a global perspective and dwell on its future prospects.
A nonmyeloablative conditioning regimen was investigated in 47 patients with hematological malignancy receiving allogeneic progenitor cells from matched, unrelated donors. The median patient age was ...44 years. The majority of patients had high-risk features, including having failed a prior transplantation (29 individuals). Twenty of the transplants were mismatched for HLA class I and/or class II alleles. Recipient conditioning consisted of 20 mg CAMPATH-1H on days −8 to −4, 30 mg/m2fludarabine on days −7 to −3, and 140 mg/m2 melphalan on day −2. Graft-versus-host disease (GVHD) prophylaxis was with cyclosporine A alone. Primary graft failure occurred in only 2 of 44 evaluable patients (4.5%). Chimerism studies in 34 patients indicated that the majority (85.3%) attained initial full donor chimerism. Only 3 patients developed grade III to IV acute GVHD, and no patients have yet developed chronic extensive GVHD. The estimated probability of nonrelapse mortality at day 100 was 14.9% (95% confidence interval CI, 4.7%-25.1%). With a median follow-up of 344 days (range, 79-830), overall and progression-free survivals at 1 year were 75.5% (95% CI, 62.8%-88.2%) and 61.5% (95% CI, 46.1%-76.8%), respectively. In summary, a nonmyeloablative regimen incorporating in vivo CAMPATH-1H is effective in promoting durable engraftment in most patients and in reducing the risk of severe GVHD following matched unrelated donor transplantation.
A novel nonmyeloablative conditioning regimen was investigated in 44 patients with hematologic malignancies. The median patient age was 41 years. Many of the patients had high-risk features, ...including 19 patients with a previous failed transplant. Recipient conditioning consisted of CAMPATH-1H, 20 mg/day on days −8 to −4; fludarabine, 30 mg/m2 on days −7 to −3; and melphalan, 140 mg/m2 on day −2. Thirty-six recipients received unmanipulated granculocyte colony-stimulating factor–mobilized peripheral blood stem cells from HLA-identical siblings, and 8 received unmanipulated marrow from matched unrelated donors. GVHD prophylaxis was with cyclosporine A alone for 38 patients and cyclosporine A plus methotrexate for 6 sibling recipients. Forty-two of the 43 evaluable patients had sustained engraftment. Results of chimerism analysis using microsatellite polymerase chain reaction indicate that 18 of 31 patients studied were full-donor chimeras while the other patients were mixed chimeras in one or more lineages. At a median follow-up of 9 months (range 3 to 29 months), 33 patients remain alive in complete remission or with no evidence of disease progression. Seven patients relapsed or progressed post-transplantation, and 4 of them subsequently died. Four patients died of regimen-related complications. There were no cases of grades III-IV acute GVHD. Only 2 patients developed grade II acute GVHD, and only 1 had chronic GVHD. The estimated probability of nonrelapse mortality was 11%. Although longer follow-up is needed to establish the long-term remission rates, this study demonstrates that this nonmyeloablative preparative regimen is associated with durable engraftment, minimal toxicity, and low incidence of GVHD.
We describe a case of severe GVHD in a 3-year-old child who had received a maternal haploidentical allograft for thalassemia major, which was refractory to several lines of therapy, including weekly ...infusion of mesenchymal cells. The child was infused paternal marrow graft from which T cells were depleted using Campath ‘in the bag’ without conditioning. There was significant improvement in gut and liver GVHD over the next few weeks along with persistent mixed biparental chimerism before the child succumbed to CMV pneumonitis. This approach hints at the possibility of using parental TCD marrow to salvage GVHD caused by a graft from the other parent, and raises the possibility of biparental grafting along the same lines as double cord transplantation.
Sirolimus has provided the option for calcineurin inhibitor (CNI)-free immunosuppressive therapy in both solid organ transplant (SOT) and hematopoietic stem cell transplantation (HSCT). However, ...long-term use of sirolimus has been reported to be associated with a high incidence of cutaneous side effects in SOT, particularly acneiform lesions.
We studied the incidence of acneiform lesions and the risk factors in 41 HSCT recipients between ages 4 and 64 years, undergoing HSCT for malignant (n = 29) and non-malignant diseases (n = 12) from haploidentical family donors.
Seven patients developed acneiform lesions at the median of 85 days (range, 45-105 days). Acneiform lesions occurred in 6/11 patients on sirolimus and in only 1/30 patients not receiving sirolimus (P = 0.001). This was more frequent in patients with non-malignant disorders (5/12 versus 2/29, P = 0.01) and those receiving graft from female donors (7/23 versus 0/18, P = 0.01).
Despite being frequently reported in SOT, this is the first such report in HSCT. Our study suggests that prolonged use of sirolimus might be associated with high incidence of acneiform lesions in haploidentical HSCT recipients with non-malignant diseases, particularly in those receiving graft from a female donor. We discuss the possible reasons for these findings and the putative mechanism of acneiform lesions in these patients.
Despite advances in transplantation techniques and immunosuppressive therapies, graft-versus-host disease (GVHD) remains a significant cause of morbidity and mortality, necessitating the use of ...innovative strategies for its prevention. T-cell activation plays a crucial role in the pathogenesis of GVHD, and T-cell costimulation blockade (COSBL) has emerged as a promising approach to prevent this devastating condition. This review aims to explore the concept of COSBL and its potential as a paradigm-shifting strategy in the prevention of GVHD, in the context of the existing modalities for the prevention of GVHD and the preclinical and clinical studies on COSBL. The unique property of abatacept (CTLA4Ig) is not just limited to dampening T-cell activation. The salutary effect of abatacept on natural killer (NK) cells and Tregs alike provides a unique opportunity to dissociate T-cell-mediated GVHD from NK cell-mediated graft-versus-leukemia. Further research is warranted to explore other modalities of COSBL, determine the optimal dosing and combinations for COSBL, and identify predictive biomarkers for patient stratification, ultimately paving the way for improved outcomes in hematopoietic cell transplantation recipients.
PDF
