Role of Donor Activating KIR-HLA Ligand-Mediated NK Cell Education Status in Control of Malignancy in Hematopoietic Cell Transplant Recipients.

Some cancers treated with allogeneic hematopoietic stem cell transplantation (HSCT) are sensitive to natural killer cell (NK) reactivity. NK function depends on activating and inhibitory receptors and is modified by NK education/licensing effect and mediated by coexpression of inhibitory killer-cell immunoglobulin-like receptor (KIR) and its corresponding HLA I ligand. We assessed activating KIR (aKIR)-based HLA I-dependent education capacity in donor NKs in 285 patients with hematological malignancies after HSCT from unrelated donors. We found significantly adverse progression-free survival (PFS) and time to progression (TTP) in patients who received transplant from donors with NKs educated by C1:KIR2DS2/3, C2:KIR2DS1, or Bw4:KIR3DS1 pairs (for PFS: hazard ratio [HR], 1.70; P = .0020, Pcorr = .0039; HR, 1.54; P = .020, Pcorr = .039; HR, 1.51; P = .020, Pcorr = .040; and for TTP: HR, 1.82; P = .049, Pcorr = .096; HR, 1.72; P = .096, Pcorr = .18; and HR, 1.65; P = .11, Pcorr = .20, respectively). Reduced PFS and TTP were significantly dependent on the number of aKIR-based education systems in donors (HR, 1.36; P = .00031, Pcorr = .00062; and HR, 1.43; P = .019, Pcorr = .038). Furthermore, the PFS and TTP were strongly adverse in patients with missing HLA ligand cognate with educating aKIR-HLA pair in donor (HR, 3.25; P = .00022, Pcorr = .00045; and HR, 3.82; P = .027, Pcorr = .054). Together, these data suggest important qualitative and quantitative role of donor NK education via aKIR-cognate HLA ligand pairs in the outcome of HSCT. Avoiding the selection of transplant donors with high numbers of aKIR-HLA-based education systems, especially for recipients with missing cognate ligand, is advisable.

Donor NK cell licensing in control of malignancy in hematopoietic stem cell transplant recipients.

Among cancers treated with allogeneic hematopoietic stem-cell transplantation (HSCT), some are sensitive to natural killer (NK) cell reactivity, described as the "missing self" recognition effect. However, this model disregarded the NK cell licensing effect, which highly increases the NK cell reactivity against tumor and is dependent on the coexpression of inhibitory killer cell immunoglobulin-like receptor (iKIR) and its corresponding HLA Class I ligand. We assessed clinical data, HLA and donor iKIR genotyping in 283 patients with myelo- and lymphoproliferative malignancies who underwent HSCT from unrelated donors. We found dramatically reduced overall survival (OS), progression free survival (PFS), and time to progression (TTP) among patients with malignant diseases with the lack of HLA ligand cognate with this iKIR involved in NK cell licensing in corresponding donor (events 83.3% vs. 39.8%, P = 0.0010; 91.6% vs. 47.7%, P = 0.00010; and 30.0% vs. 17.3%, P = 0.013, for OS, PFS, and TTP, respectively). The extremely adverse PFS have withstand the correction when patient group was restricted to HLA mismatched donor-recipient pairs. The incidence of aGvHD was comparable in two groups of patients. In malignant patients after HSCT the missing HLA ligand for iKIR involved in NK cell licensing in corresponding donor ("missing licensing proof") induced extremely adverse survival of the patients due to the progression of malignancy and not to the aGvHD. Avoiding the selection of HSCT donors with the "missing licensing proof" in the malignant patient is strongly advisable.

[Analysis of the prevalence of HBV markers relevant to the risk of reactivation of infection in patients with hematologic diseases]. / Analiza wystepowania markerów wirusa HBV istotnych dla ryzyka reaktywacji zakazenia u osób z chorobami hematologicznymi.

The study assessed the incidence of HBV markers (HBsAg, anti-HBc, anti-HBs) important for determination of the risk of reactivation of infection, with particular interest of occult infection (presence of HBV DNA in the absence of HBsAg) in patients treated at the Institute of Hematology and Transfusion Medicine. Anti-HBc frequency was correlated with the age and sex of patients. HBsAg was detected in 16/468 examined patients, 98/468 (21%) were anti-HBc positive. HBV DNA was detected in 41/98 anti-HBc positives; in 13 simultaneously with HBsAg. 28 patients had occult HBV infection (HBV DNA+/HBsAg). Antibody to HBsAg was detected in 163/430 (38%) patients, 81 out of them on protective level (> 100 IU/l). It was shown that occult HBV infection occurs in approximately 6% of patients. In most of them the protective levels of anti-HBs are detected.

Clinical evaluation of busulfan, cladribine and alemtuzumab as reduced intensity conditioning for stem cell transplantation.

BACKGROUND: Reduced intensity conditioning before allogeneic stem cell transplantation is an option for patients not eligible for myeloablative standard procedure. In recent years alemtuzumab, an anti CD52 antibody has gained much interest in this setting for its particular immunosuppresive properties.
MATERIAL/METHODS: We evaluated clinical results of allogeneic stem cell transplantation in nine patients (2 females and 7 males, median age 51, range 26-65) after reduced intensity conditioning consisting of busulfan, cladribine and alemtuzumab. The donors were HLA identical siblings (7) or unrelated (2). Peripheral blood stem cells mobilized with G-CSF were used. Cyclosporine alone was used for GvHD prevention after transplantation. RESULTS: 4 patients (44%) are alive at 24-42 months after transplantation and 3 patients (33%) remain in complete remission at 26-42 months, including one after donor lymphocyte infusion for decreasing hematopoietic chimerism. No acute graft versus host disease was observed and only 3 patients (33%) developed chronic graft versus host disease. High rate (56%) of CMV reactivation and 2 cases of tuberculosis were noted. All deceased patents died due to disease relapse and progression.
CONCLUSIONS: Reduced intensity conditioning with alemtuzumab and allogeneic stem cell transplantation offers potential cure to patients not eligible for conventional procedure. Better methodology of chimerism evaluation is mandatory to improve results of transplantations by implementation donor lymphocyte infusions.

Role of donor HLA class I mismatch, KIR-ligand mismatch and HLA:KIR pairings in hematological malignancy relapse after unrelated hematopoietic stem cell transplantation.

HLA are functional in cancer immunosurveillance in adaptive and innate immunity pathways. In unrelated hematopoietic stem cell transplantation (HSCT) in 688 patients with hematological malignancies we compared antitumor efficacy of transplant in three models including the level of: (a) donor-recipient HLA class I mismatch, (b) KIR-ligand mismatch, (c) post-transplant cognate HLA:KIR pairing. The effects were directly compared in multivariate models with backward elimination including all three effects in initial model. In final multivariate model HLA mismatch and KIR-ligand mismatch levels were eliminated and HLA:KIR-dependent NK cell licensing effect remained independent prognostic factor for DFS, relapse/progression incidence, and overall survival (OS). These results suggested that NK cell licensing via cognate HLA:KIR pairs is primarily functional in cancer immunosurveillance in HSCT.

HLA-inferred extended haplotype disparity level is more relevant than the level of HLA mismatch alone for the patients survival and GvHD in T cell-replate hematopoietic stem cell transplantation from unrelated donor.

Serious risks in unrelated hematopoietic stem cell transplantation (HSCT) including graft versus host disease (GvHD) and mortality are associated with HLA disparity between donor and recipient. The increased risks might be dependent on disparity in not-routinely-tested multiple polymorphisms in genetically dense MHC region, being organized in combinations of two extended MHC haplotypes (Ehp). We assessed the clinical role of donor-recipient Ehp disparity levels in N = 889 patients by the population-based detection of HLA allele phase mismatch. We found increased GvHD incidences and mortality rates with increasing Ehp mismatch level even with the same HLA mismatch level. In multivariate analysis HLA mismatch levels were excluded from models and Ehp disparity level remained independent prognostic factor for high grade acute GvHD (p = 0.000037, HR = 10.68, 95%CI 5.50-32.5) and extended chronic GvHD (p < 0.000001, HR = 15.51, CI95% 5.36-44.8). In group with single HLA mismatch, patients with double Ehp disparity had worse 5-year overall survival (45% vs. 56%, p = 0.00065, HR = 4.05, CI95% 1.69-9.71) and non-relapse mortality (40% vs. 31%, p = 0.00037, HR = 5.63, CI95% 2.04-15.5) than patients with single Ehp disparity. We conclude that Ehp-linked factors contribute to the high morbidity and mortality in recipients given HLA-mismatched unrelated transplant and Ehp matching should be considered in clinical HSCT.

Limited predictive value of real-time quantitative PCR cytomegalovirus monitoring in the blood. Fatal CMV pneumonia in an autologous stem cell transplant recipient previously treated with alemtuzumab.

BACKGROUND: Patients treated with alemtuzumab are at very high risk for cytomegalovirus (CMV) reactivation. Also, in those who develop reactivation short time before stem cell transplantation the risk of fatal complications is extremely high. CASE REPORT: We describe a 21-year-old patient with anaplastic large T-cell lymphoma who developed CMV reactivation after alemtuzumab treatment and received high-dose chemotherapy with autologous stein cell transplantation for progressive disease and severe bone marrow aplasia. Blood samples of the patient were tested regularly for CMV reactivation with real-time quantitative PCR. Even though it is considered the most sensitive available method it did not allow us to predict in advance development of fatal CMV pneumonia in this patient. CONCLUSIONS: The case report illustrates limitations of prognostic value of quantitative real-time PCR CMV assessment in blood samples.

Predictive value of RT-PCR PML-RARA transcript monitoring for extramedullary relapse of acute promyelocytic leukemia in the pleura, heart and pericardium after allogeneic SCT.

BACKGROUND: We report a patient with acute promyelocytic leukemia (APL) relapse in extremely rare sites--the pleura, heart and pericardium without evidence of bone marrow infiltration and with molecular evidence of disease after allogeneic stem cell transplantation (alloSCT). CASE DESCRIPTION: Presented patient underwent alloSCT in second complete hematological and cytogenetic remission with presence of promyelocytic leukemia-retinoic acid receptor A (PML-RARA) detected in reverse transcription-polymerase chain reaction (RT-PCR) with sensitivity of 10(-2). After transplant, this patient remained in complete hematological and cytogenetic remission but nested RT-PCR assays with detection thresholds of 10(-3)/10(-4) were positive for PML-RARA rearranged gene even chimerism tests showed 100% of donor profile. He was in a very good clinical condition and presented symptoms of transient limited chronic graft vs. host disease. Twenty one months after transplant, the leukemic relapse in the pleura, heart and pericardium was diagnosed. At that time, PML-RARA transcript detected in RT-PCR assay (10(-2)) was positive for the first time after transplant. During salvage chemotherapy he died because of cardiogenic shock. CONCLUSIONS: We conclude that detection of PML-RARA after alloSCT should be indication insightful diagnosis of medullary or extramedullary (EM) relapse. The imaging techniques of all possible sites of APL EM relapse have to be included.

Guillain-Barre syndrome--pathological connection with GvHD after allogeneic bone marrow transplantation.

The Guillain-Barre syndrome (GBS) could be a manifestation of neurotoxicity caused by multiple factors due to allogeneic bone marrow transplantations (alloBMT). In this paper we present a case of a 40-year old woman with chronic myeloid leukemia after alloBMT from her HLA identical brother. She developed the second grade of acute hepatic graft versus host disease (GvHD) shortly after alloBMT followed by chronic form. We observed Guillain-Barre syndrome probably triggering by GvHD in this patient.

The significance of oral labial biopsy in hepatic graft-versus-host disease diagnosis in patients following allogeneic hematopoietic stem cell transplantation--a preliminary report.

BACKGROUND: Graft-versus-host disease (GvHD) is the most important complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT) responsible for increased mortality. Recent studies have discussed the use of oral GvHD screening tests in the diagnosis of systemic GvHD. This is the first study of the significance of oral labial biopsy in diagnosis of hepatic graft-versus-host disease (H-GvHD) following allo-HSCT. MATERIAL/METHODS: Twenty-one patients after alloHSCT were selected: 12 patients with H-GvHD established clinically and in laboratory tests, and 9 patients without features of GvHD (control group). Histopathological and immunohistochemical evaluations of tissue samples included the following: 15 samples of oral mucosa (OM), 19 of lip salivary glands (LSG), and 5 of the liver, were performed in both groups. RESULTS: All patients had clinically normal oral mucosa and 4 patients with H-GvHD manifested with xerostomia symptoms. Histological examination of LSG and/or OM confirmed the GvHD diagnosis in 9 of 12 patients with H-GvHD. The microscopic changes included: mild inflammatory lymphocytic infiltrates and apoptotic bodies in OM, and inflammatory infiltrates of mild degree with minimal CD8+ T cells predominance in the invaded ducts epithelium in LSG. In the control group, 4 of 9 patients had mild chronic inflammation, which did not fulfill the criteria of GvHD. The histopathological image of liver biopsies correlated with the clinical GvHD diagnosis. CONCLUSIONS: The microscopic evaluation of LSG and/or OM biopsy confirms the clinical diagnosis of H-GvHD, regardless of the absence of clinical oral symptoms of GVHD. The histopathological features of oral GvHD may be subtle; the diagnosis requires a clinico-pathological and laboratory approach to exclude the other diseases with similar histopathological features.