Riitta Niittyvuopio

Pregnancy in essential thrombocythaemia : experience with 40 pregnancies

Abstract:  In this study, the course of 40 pregnancies in 16 women with essential thrombocythaemia (ET) was analysed retrospectively. Of the pregnancies, 45% were complicated, 55% uncomplicated, and 62% resulted in live birth. The most common complication was spontaneous abortion during the first trimester seen in 33% of all pregnancies and comprising 72% of all complications. Two intrauterine foetal deaths occurred at weeks 22 and 28. Three pregnancies were complicated by eclampsia or pre‐eclampsia. Nine of 16 women with 29 pregnancies had at least one complicated pregnancy. In seven of 16 women, all 11 pregnancies were uneventful. The non‐pregnancy‐related symptoms of ET or the platelet count before conception or during pregnancy did not correlate with the risk of pregnancy complications. Treatment with low‐dose acetylsalicylic acid (ASA) alone during pregnancy or platelet‐lowering drugs before or during pregnancy reduced the risk of complications.

Donor haplotype B of NK KIR receptor reduces the relapse risk in HLA-identical sibling hematopoietic stem cell transplantation of AML patients

Successful allogeneic hematopoietic stem cell transplantation (HSCT) depends not only on good HLA match but also on T-cell mediated graft-versus-leukemia (GvL) effect. Natural killer (NK) cells are able to kill malignant cells by receiving activation signal from the killer-cell immunoglobulin-like receptors (KIR) recognizing HLA molecules on a cancer cell. It has been recently reported that the risk of relapse in allogeneic hematopoietic stem cell transplantation (HSCT) is reduced in acute myeloid leukemia (AML) patients whose donors have several activating KIR genes or KIR B-motifs in unrelated donor setting, obviously due to enhanced GvL effect by NK cells. We studied the effect on relapse rate of donor KIR haplotypes in the HLA-identical adult sibling HSCT, done in a single center, in Helsinki University Central Hospital, Helsinki, Finland. Altogether, 134 patients with 6 different diagnoses were identified. Their donors were KIR genotyped using the Luminex and the SSP techniques. The clinical endpoint, that is, occurrence of relapse, was compared with the presence or absence of single KIR genes. Also, time from transplantation to relapse was analyzed. The patients with AML whose donors have KIR2DL2 or KIR2DS2 had statistically significantly longer relapse-free survival (P = 0.015). Our data support previous reports that donors with KIR B-haplotype defining genes have a lower occurrence of relapse in HSCT of AML patients. Determination of donor KIR haplotypes could be a useful addition for a risk assessment of HSCT especially in AML patients.

The predictive value of megakaryocytic and erythroid colony formation and platelet function tests on the risk of thromboembolic and bleeding complications in essential thrombocythaemia.

The predictive value of spontaneous in vitro colony formation of megakaryocytic and erythroid progenitors (154 patients), and defective platelet aggregation responses (55 patients) on the risk of thrombohaemorrhagic complications in patients with essential thrombocythaemia (ET) was evaluated retrospectively. In the in vitro cultures of haematopoietic progenitors, 114/154 patients (74%) showed either spontaneous megakaryocytic or erythroid colony formation or both. Forty‐three per cent of patients with any spontaneous colony growth and only 20% of those without this phenomenon had an arterial thrombosis at diagnosis or during the follow‐up (P = 0.02). In the whole patient group neither spontaneous megakaryocytic nor spontaneous erythroid colony formation alone predicted the risk of arterial thrombosis. In patients younger than 45 yr of age, the prognostic value of spontaneous megakaryocytic growth was statistically significant: 44% of the patients with spontaneous megakaryocytic colony formation, but only 14% of those without it, experienced arterial thrombosis (P = 0.04). The presence of spontaneous colony formation had no effect on the risk of bleeding complications. Forty‐one of the 55 patients (75%) showed abnormalities in the platelet aggregation responses. There was no statistically significant correlation between the platelet function response and the risk of bleeding or thrombotic complications. No correlation was found between the platelet aggregation responses and the presence of spontaneous colony growth. In conclusion, spontaneous colony formation indicated an increased risk of thrombohaemorragic events but the platelet function test had no predictive value for these complications.

Good responses but high TRM in adult patients after MSC therapy for GvHD.

Despite many advances in the field of allogeneic hematopoietic stem cell transplantation (alloHSCT) only limited progress has been made in the treatment of steroid-refractory GvHD. Around 40–80% of transplant recipients experience grade II–IV acute GvHD (aGvHD), and a sustained response to first line corticosteroid treatment is achieved only in half of them. Grade IV steroidrefractory aGvHD is associated with particularly poor prognosis with a long-term survival of less than 10%. We report the outcome of 30 consecutive adult and pediatric patients who were treated for steroid-refractory GvHD with third party bone marrow-derived, platelet-lysate (PL)-expanded mesenchymal stem cells (MSCs) in a prospective single-arm study. Adult patients had undergone allogeneic SCT for a malignant or non-malignant disease at Turku University Hospital or Helsinki University Hospital and pediatric patients at Helsinki Children’s Hospital. aGvHD was graded according to the Glucksberg criteria and indications for MSC treatment were steroid resistance defined as progression or lack of response after five days of treatment with methylprednisolone 2 mg/kg, or recurrent aGvHD, while tapering steroid. Chronic GvHD (cGvHD) was graded according to the consensus criteria by the National Institute of Health. Indications for MSC treatment in cGvHD were steroid resistance defined as a lack of response after 30 days on treatment, or steroid dependency defined as a progression when steroid was tapered. All patients or their legal guardians provided written informed consent for MSC treatment. Allogeneic bone-marrow derived MSCs (LY-MSCs) were produced in the GMP facility of the Advanced Cell Therapy Centre, Finnish Red Cross Blood Service (FRCBS), Helsinki, Finland. The process development and main features of the clinical-grade LY-MSC production method based on platelet lysate has been described previously and detailed protocol is presented in Supplementary Information. The aim was to provide a total of 6 doses of MSCs to each patient, administered according to a bi-weekly (aGvHD and cGvHD) or once-weekly (cGvHD) schedule. The target dose for each infusion was 2 × 10 cells/kg recipient body weight. In aGvHD, responses to MSC therapy were evaluated on day 28 after the first MSC dose. At this time point, organ specific stage and overall grade were recorded, and the responses were categorized as complete response (CR, complete resolution of symptoms), very good partial response (VGPR, decrease in overall grade ⩾ 2 grades), partial response (PR, improvement less than VGPR) and no response (NR). Patients were considered responders if they demonstrated at least PR. In cGvHD, organ specific and global severity scores were assessed at three months post treatment, and responses were classified as CR (resolution of all symptoms relating to cGvHD), PR (decrease in overall severity score or decrease of ⩾ 2 points in the sum of organ specific scores) and NR. Most patients received mold-active antifungal prophylaxis in addition to viral and pneumocystis pneumonia prophylaxis. Statistical analyses were performed using the SPSS software package (IBM SPSS Statistics 21). Survival was calculated from the onset of GvHD to death. Survival curves were estimated with the Kaplan–Meier method and the log-rank test was applied to

A randomized study of cyclosporine and methotrexate with or without methylprednisolone for the prevention of graft-versus-host disease: Improved long-term survival with triple prophylaxis: GVHD Prevention

In a previously published study, the authors randomized 108 adult patients with a malignant hematologic disorder undergoing allogeneic bone marrow transplantation from a human leukocyte antigen‐identical sibling to receive methylprednisolone (53 patients; MP+) or not to receive methylprednisolone (55 patients; MP‐) as a part of graft‐versus‐host disease (GVHD) prophylaxis. All patients received cyclosporine and methotrexate. The cumulative incidence of acute GVHD was found to be significantly lower among the patients given MP.

Extracorporeal photopheresis in the treatment of acute graft-versus-host disease: a single-center experience: ECP FOR ACUTE GVHD

Steroid‐refractory acute graft‐versus‐host disease (aGVHD) is a serious complication after hematopoietic stem cell transplantation. The long‐term outcome of the patients is poor. Various immunosuppressive agents have been proposed as the second‐line therapy but none of them has turned out more effective than the others. Extracorporeal photopheresis (ECP) is a treatment option that does not predispose the patients to severe side effects of the immunosuppressive drugs.

Hidden genomic MHC disparity between HLA-matched sibling pairs in hematopoietic stem cell transplantation

Matching classical HLA alleles between donor and recipient is an important factor in avoiding adverse immunological effects in HSCT. Siblings with no differences in HLA alleles, either due to identical-by-state or identical-by-descent status, are considered to be optimal donors. We carried out a retrospective genomic sequence and SNP analysis of 336 fully HLA-A, -B, -DRB1 matched and 14 partially HLA-matched sibling HSCT pairs to determine the level of undetected mismatching within the MHC segment as well as to map their recombination sites. The genomic sequence of 34 genes locating in the MHC region revealed allelic mismatching at 1 to 8 additional genes in partially HLA-matched pairs. Also, fully matched pairs were found to have mismatching either at HLA-DPB1 or at non-HLA region within the MHC segment. Altogether, 3.9% of fully HLA-matched HSCT pairs had large genomic mismatching in the MHC segment. Recombination sites mapped to certain restricted locations. The number of mismatched nucleotides correlated with the risk of GvHD supporting the central role of full HLA matching in HSCT. High-density genome analysis revealed that fully HLA-matched siblings may not have identical MHC segments and even single allelic mismatching at any classical HLA gene often implies larger genomic differences along MHC.

Genomic prediction of relapse in recipients of allogeneic haematopoietic stem cell transplantation

Allogeneic haematopoietic stem cell transplantation currently represents the primary potentially curative treatment for cancers of the blood and bone marrow. While relapse occurs in approximately 30% of patients, few risk-modifying genetic variants have been identified. The present study evaluates the predictive potential of patient genetics on relapse risk in a genome-wide manner. We studied 151 graft recipients with HLA-matched sibling donors by sequencing the whole-exome, active immunoregulatory regions, and the full MHC region. To assess the predictive capability and contributions of SNPs and INDELs, we employed machine learning and a feature selection approach in a cross-validation framework to discover the most informative variants while controlling against overfitting. Our results show that germline genetic polymorphisms in patients entail a significant contribution to relapse risk, as judged by the predictive performance of the model (AUC = 0.72 [95% CI: 0.63–0.81]). Furthermore, the top contributing variants were predictive in two independent replication cohorts (n = 258 and n = 125) from the same population. The results can help elucidate relapse mechanisms and suggest novel therapeutic targets. A computational genomic model could provide a step toward individualized prognostic risk assessment, particularly when accompanied by other data modalities.

Incidence and risk factors of secondary cancers after allogeneic stem cell transplantation: analysis of a single centre cohort with a long follow-up

As the long-term outcome of allogeneic stem cell transplantation (allo-SCT) has improved, the significance of post-transplant late effects is growing. In long-term survivors, secondary solid cancers have been reported to appear at least at twice the rate expected in the general population [1-4]. The reported cumulative incidence of secondary cancers varies from 1 to 11% at 10 years and from 2−12% at 15 years [1, 5, 6]. The 5-year overall survival (OS) rate from the diagnosis of a secondary malignancy is 42−50%, but the prognosis varies according to the type of the cancer [7, 8]. Risk factors for secondary cancers include the use of total body irradiation (TBI), the intensity of the conditioning regimen, chronic GvHD (cGvHD), and the age at transplantation, but the data are conflicting [1, 4, 6, 9] We investigated the incidence, the subtypes, and the risk factors of secondary cancers in patients aged over 16 who underwent allo-SCT in Helsinki University Hospital between January 1996 and December 2014. Patients with haploidentical donors, cord blood grafts, or double alloSCT (34 in total) were excluded. Cyclosporine A and methotrexate were used as GvHD prophylaxis. We included all secondary malignancies, except for post-transplant lymphoproliferation and non-melanoma skin cancers. The follow-up of the living patients was to the end of May 2017. The patient data were collected from the EBMT Promise database. The incidence rates of specific cancer types in Finland were obtained from the Finnish Cancer Registry, which maintains a database on cancers detected in Finland (population 5.5 million). Descriptive cross-tabulations were created between the response variable (incidence of secondary malignancy) and the predefined potential risk factors (age at transplantation, gender, diagnosis, conditioning intensity, TBI, anti-thymocyte globulin as a part of the conditioning, graft type, donor type, acute GvHD (aGvHD), aGvHD ≥ gr 2, cGvHD, and extensive cGvHD). The effect of the risk factors was first analysed with univariate logistic regression. Second, a multivariate logistic regression model was fitted, where the variables found meaningful (P value < 0.1) in the univariate analysis were inserted into the model as fixed terms. As both cGvHD (any grade) and extensive cGvHD were significant in the univariate analysis, only the one (cGvHD any grade) with the lower P value was included in the multivariate model. Odds ratios (OR) and their 95% CIs were used to quantify the results of the logistic regression models. The ORs are constructed for the probability for the secondary cancer to occur. The cumulative incidence of secondary cancers and OS were estimated by the Kaplan-Meier method where death or the end of the follow-up time were competitive events, whichever came first. The incidence rates of secondary cancers were evaluated by calculating the incidence rate per 100 000 person-years applying a formula: (number of events/sum of follow-up times in years of the sample population)*100 000. This approach was taken to be able to compare with rates from the Finnish Cancer Registry. The CIs for the incidence rates /100 000 person-years were calculated using a Poisson regression model. Standardised incidence ratios (SIR) of secondary cancers were calculated as the ratio of the observed incidence rates to the expected population incidence rates. P values of < 0.05 were considered statistically significant, all the presented P values are two-tailed. Statistical analyses were carried out with SAS for Windows (version 9.3; SAS Institute, Cary, NC, USA). * Eeva Martelin eeva.martelin@hus.fi

Diagnosis of veno-occlusive disease/sinusoidal obstruction syndrome of the liver: problems of interpretation.

Diagnosis of veno-occlusive disease/sinusoidal obstruction syndrome of the liver: problems of interpretation