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Pixantrone beyond monotherapy: a review.

To, 18/07/2019 - 23:21

Pixantrone beyond monotherapy: a review.

Ann Hematol. 2019 Jul 17;:

Authors: Barrenetxea Lekue C, Grasso Cicala S, Leppä S, Stauffer Larsen T, Herráez Rodríguez S, Alonso Caballero C, Jørgensen JM, Toldbod H, Leal Martínez I, D'Amore F

Abstract
Outcomes for patients with non-Hodgkin's lymphoma (NHL) that proves refractory to treatment remain poor. Treatment of such patients is individualized and can include enrolment in a clinical trial of novel agents or use of one of a wide array of drug regimens. Initial treatment with anthracyclines such as doxorubicin limits options at later stages of treatment because of anthracycline-related cumulative cardiotoxicity. The aza-anthracenedione pixantrone was developed to reduce the likelihood of cardiotoxicity without compromising efficacy and is currently conditionally approved for use as monotherapy in patients with multiply-relapsed or refractory aggressive B cell NHL. The use of pixantrone in combination therapy, often to replace doxorubicin or mitoxantrone, has or is currently being investigated in numerous studies in patients with aggressive or indolent NHL and is the focus of this review. These include the R-CPOP regimen (rituximab, cyclophosphamide, pixantrone, vincristine, prednisone) for aggressive NHL in the first-line setting, including a study in elderly patients with limited cardiac function, and for patients with relapsed NHL with prior anthracycline exposure; the PSHAP regimen (pixantrone, cytarabine, prednisone, cisplatin), also in the latter setting; the PREBen/PEBen regimen (pixantrone, bendamustine and etoposide with or without rituximab) as salvage therapy; and pixantrone in combination with fludarabine, dexamethasone, and rituximab (FPD-R) for relapsed indolent NHL.

PMID: 31312929 [PubMed - as supplied by publisher]

The European Blood and Marrow Transplantation Textbook for Nurses: Under the Auspices of EBMT

To, 18/07/2019 - 23:21

The European Blood and Marrow Transplantation Textbook for Nurses: Under the Auspices of EBMT

Book. 2018

Authors: Kenyon M, Babic A

Abstract
HSCT is a complex procedure, which involves a long and complicated pathway for the patient and the intervention of many health professionals. Within this multidisciplinary team, the transplant coordinator, usually a nurse, is the ‘essential marrow’, the heart and the vital backbone of this procedure; they are an essential transplant ingredient facilitating a fluidity of the pathway and a good transmission of information. Written information about the procedure is beneficial for patients either prior to clinic visit or during clinic to allow the patients and relatives to reflect on conversations. Transplantation carries a significant risk of morbidity and mortality, and these should be considered regarding the ‘need’ to transplant, based upon risk of disease, versus risk of the transplant. Pre-transplant assessments must also be undertaken, and the results of these along with suitable donor medical clearance and cell availability are essential to ascertain that transplant is a valid option and can proceed safely. Dealing with fertility preservation upon diagnosis of cancer is often challenging; this issue is even more complex for paediatric patients. PDWP recommends that counselling about fertility preservation opportunities should be offered to each patient receiving HSCT. This chapter will also focus on vascular access for optimal treatment of haematology patients because stem cell treatment cannot be performed without it. Constant advances in haematology have raised challenging ethical dilemmas concerning end of life, palliative care, patient information, donor concerns and impartiality and issues related to the risk we run to our patients. Nurses provide a key role in patient education, providing pre- and post-transplant advocacy and counselling, plan hospitalisations and consultations. They also act as educators and role models to nursing students and share knowledge in accordance with local policies and JACIE guidelines.


PMID: 31314318

Outcome of hematopoietic cell transplantation for DNA double-strand break repair disorders.

Ke, 17/07/2019 - 23:21
Related Articles

Outcome of hematopoietic cell transplantation for DNA double-strand break repair disorders.

J Allergy Clin Immunol. 2018 01;141(1):322-328.e10

Authors: Slack J, Albert MH, Balashov D, Belohradsky BH, Bertaina A, Bleesing J, Booth C, Buechner J, Buckley RH, Ouachée-Chardin M, Deripapa E, Drabko K, Eapen M, Feuchtinger T, Finocchi A, Gaspar HB, Ghosh S, Gillio A, Gonzalez-Granado LI, Grunebaum E, Güngör T, Heilmann C, Helminen M, Higuchi K, Imai K, Kalwak K, Kanazawa N, Karasu G, Kucuk ZY, Laberko A, Lange A, Mahlaoui N, Meisel R, Moshous D, Muramatsu H, Parikh S, Pasic S, Schmid I, Schuetz C, Schulz A, Schultz KR, Shaw PJ, Slatter MA, Sykora KW, Tamura S, Taskinen M, Wawer A, Wolska-Kuśnierz B, Cowan MJ, Fischer A, Gennery AR, Inborn Errors Working Party of the European Society for Blood and Marrow Transplantation and the European Society for Immunodeficiencies, Stem Cell Transplant for Immunodeficiencies in Europe (SCETIDE), Center for International Blood and Marrow Transplant Research, Primary Immunodeficiency Treatment Consortium

Abstract
BACKGROUND: Rare DNA breakage repair disorders predispose to infection and lymphoreticular malignancies. Hematopoietic cell transplantation (HCT) is curative, but coadministered chemotherapy or radiotherapy is damaging because of systemic radiosensitivity. We collected HCT outcome data for Nijmegen breakage syndrome, DNA ligase IV deficiency, Cernunnos-XRCC4-like factor (Cernunnos-XLF) deficiency, and ataxia-telangiectasia (AT).
METHODS: Data from 38 centers worldwide, including indication, donor, conditioning regimen, graft-versus-host disease, and outcome, were analyzed. Conditioning was classified as myeloablative conditioning (MAC) if it contained radiotherapy or alkylators and reduced-intensity conditioning (RIC) if no alkylators and/or 150 mg/m2 fludarabine or less and 40 mg/kg cyclophosphamide or less were used.
RESULTS: Fifty-five new, 14 updated, and 18 previously published patients were analyzed. Median age at HCT was 48 months (range, 1.5-552 months). Twenty-nine patients underwent transplantation for infection, 21 had malignancy, 13 had bone marrow failure, 13 received pre-emptive transplantation, 5 had multiple indications, and 6 had no information. Twenty-two received MAC, 59 received RIC, and 4 were infused; information was unavailable for 2 patients. Seventy-three of 77 patients with DNA ligase IV deficiency, Cernunnos-XLF deficiency, or Nijmegen breakage syndrome received conditioning. Survival was 53 (69%) of 77 and was worse for those receiving MAC than for those receiving RIC (P = .006). Most deaths occurred early after transplantation, suggesting poor tolerance of conditioning. Survival in patients with AT was 25%. Forty-one (49%) of 83 patients experienced acute GvHD, which was less frequent in those receiving RIC compared with those receiving MAC (26/56 [46%] vs 12/21 [57%], P = .45). Median follow-up was 35 months (range, 2-168 months). No secondary malignancies were reported during 15 years of follow-up. Growth and developmental delay remained after HCT; immune-mediated complications resolved.
CONCLUSION: RIC HCT resolves DNA repair disorder-associated immunodeficiency. Long-term follow-up is required for secondary malignancy surveillance. Routine HCT for AT is not recommended.

PMID: 28392333 [PubMed - indexed for MEDLINE]

The prognostic impact of the cytomegalovirus serostatus in patients with chronic hematological malignancies after allogeneic hematopoietic stem cell transplantation: a report from the Infectious Diseases Working Party of EBMT.

Ti, 16/07/2019 - 23:20
Related Articles

The prognostic impact of the cytomegalovirus serostatus in patients with chronic hematological malignancies after allogeneic hematopoietic stem cell transplantation: a report from the Infectious Diseases Working Party of EBMT.

Ann Hematol. 2019 Jul;98(7):1755-1763

Authors: Schmidt-Hieber M, Tridello G, Ljungman P, Mikulska M, Knelange N, Blaise D, Socié G, Volin L, Blijlevens N, Fegueux N, Yakoub-Agha I, Forcade E, Maertens J, Chevallier P, Passweg J, Cornelissen J, Russell N, Craddock C, Bourhis JH, Marchand T, Reményi P, Cahn JY, Michallet M, Montoto S, Kröger N, Glaß B, Styczynski J

Abstract
It has been shown recently that donor and/or recipient cytomegalovirus (CMV) seropositivity is associated with a significant overall survival (OS) decline in acute leukemia patients who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT). We now analyzed the prognostic impact of the donor/recipient CMV serostatus in 6968 patients with chronic hematological malignancies who underwent allo-HSCT. Donor and/or recipient CMV seropositivity was associated with a significantly reduced 2-year progression-free survival (PFS, 50% vs. 52%, p = 0.03) and OS (62% vs. 65%, p = 0.01). Multivariate Cox regression analyses showed an independent negative prognostic impact of donor and/or recipient CMV seropositivity on PFS (HR, 1.1; 95% CI, 1.0-1.2; p = 0.03), OS (HR, 1.1; 95% CI, 1.0-1.2; p = 0.003), and non-relapse mortality (HR, 1.2; 95% CI, 1.0-1.3; p = 0.02). OS decline was strongest for CMV-seropositive recipients with a CMV-seronegative donor (HR, 1.2; 95% CI, 1.1-1.3), followed by CMV-seropositive patients with a CMV-seropositive donor (HR, 1.1; 95% CI, 1.0-1.2). Conversely, OS did not differ significantly between CMV-seronegative recipients allografted from a CMV-seropositive donor (HR, 1.0; 95% CI, 0.9-1.2) and patients with donor/recipient CMV seronegativity (p = 0.001 for the four groups together). Non-relapse mortality was also significantly (p = 0.01) higher for CMV-seropositive patients with a CMV-seronegative graft (HR, 1.2; 95% CI, 1.1-1.4) than for CMV-seropositive patients with a CMV-seropositive graft (HR, 1.1; 95% CI, 0.9-1.2) or CMV-seronegative recipients with a CMV-seropositive graft (HR, 1.0; 95% CI, 0.8-1.2). Donor and/or recipient CMV seropositivity still results in an OS decline in patients with chronic hematological malignancies who have undergone allo-HSCT. However, this OS decline seems to be lower than that described for acute leukemia patients previously.

PMID: 30993417 [PubMed - indexed for MEDLINE]

Complex and monosomal karyotype are distinct cytogenetic entities with an adverse prognostic impact in paediatric acute myeloid leukaemia. A NOPHO-DBH-AML study.

Ti, 16/07/2019 - 23:20
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Complex and monosomal karyotype are distinct cytogenetic entities with an adverse prognostic impact in paediatric acute myeloid leukaemia. A NOPHO-DBH-AML study.

Br J Haematol. 2018 11;183(4):618-628

Authors: Bager N, Juul-Dam KL, Sandahl JD, Abrahamsson J, Beverloo B, de Bont ESJM, Ha SY, Jahnukainen K, Jónsson ÓG, Kaspers GL, Kovalova Z, Lausen B, De Moerloose B, Noren-Nyström U, Palle J, Saks K, Zeller B, Kjeldsen E, Hasle H

Abstract
Data on occurrence, genetic characteristics and prognostic impact of complex and monosomal karyotype (CK/MK) in children with acute myeloid leukaemia (AML) are scarce. We studied CK and MK in a large unselected cohort of childhood AML patients diagnosed and treated according to Nordic Society for Paediatric Haematology and Oncology (NOPHO)-AML protocols 1993-2015. In total, 800 patients with de novo AML were included. CK was found in 122 (15%) and MK in 41 (5%) patients. CK and MK patients were young (median age 2·1 and 3·3 years, respectively) and frequently had FAB M7 morphology (24% and 22%, respectively). Refractory disease was more common in MK patients (15% vs. 4%) and stem cell transplantation in first complete remission was more frequent (32% vs. 19%) compared with non-CK/non-MK patients. CK showed no association with refractory disease but was an independent predictor of an inferior event-free survival (EFS; hazard ratio [HR] 1·43, P = 0·03) and overall survival (OS; HR 1·48, P = 0·01). MK was associated with a poor EFS (HR 1·57, P = 0·03) but did not show an inferior OS compared to non-MK patients (HR 1·14, P = 0·62). In a large paediatric cohort, we characterized AML with non-recurrent abnormal karyotype and unravelled the adverse impact of CK and MK on prognosis.

PMID: 30406946 [PubMed - indexed for MEDLINE]

Variability of nutritional practices in peritransplant period after allogeneic hematopoietic stem cell transplantation: a survey by the Complications and Quality of Life Working Party of the EBMT.

Ti, 16/07/2019 - 23:20
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Variability of nutritional practices in peritransplant period after allogeneic hematopoietic stem cell transplantation: a survey by the Complications and Quality of Life Working Party of the EBMT.

Bone Marrow Transplant. 2018 08;53(8):1030-1037

Authors: Peric Z, Botti S, Stringer J, Krawczyk J, van der Werf S, van Biezen A, Aljurf M, Murray J, Liptrott S, Greenfield DM, Duarte RF, Ruutu T, Basak GW

Abstract
Recommendations on screening and nutritional support for patients undergoing hematopoietic stem cell transplantation (HSCT) have been presented by international nutritional societies, but nutritional practices remain poorly standardized. Following the general policy of the European Society for Blood and Marrow Transplantation (EBMT) to standardize transplantation procedures, the Complications and Quality of Life Working Party and Nursing Research Group carried out a survey among all EBMT centers about their current nutritional practices. The aim of this study was to better understand current practices, differences from available guidelines, and possible barriers for recommended nutritional therapy. Responses from 90 centers (19%) from 23 countries were received. We observed a marked variability in nutritional care between EBMT centers and a substantial lack of standardized operating procedures in screening patients for malnutrition and management of gastrointestinal GVHD. Furthermore, our study confirmed neutropenic diet as standard of care in most centers as well a preference for parenteral nutritional support over enteral. On the basis of these findings, future EBMT efforts will focus on better implementation of international nutritional guidelines into clinical practice.

PMID: 29515252 [PubMed - indexed for MEDLINE]

Rituximab plus bendamustine or chlorambucil for chronic lymphocytic leukemia: primary analysis of the randomized, open-label MABLE study.

Ti, 16/07/2019 - 23:20
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Rituximab plus bendamustine or chlorambucil for chronic lymphocytic leukemia: primary analysis of the randomized, open-label MABLE study.

Haematologica. 2018 04;103(4):698-706

Authors: Michallet AS, Aktan M, Hiddemann W, Ilhan O, Johansson P, Laribi K, Meddeb B, Moreno C, Raposo J, Schuh A, Ünal A, Widenius T, Bernhardt A, Kellershohn K, Messeri D, Osborne S, Leblond V

Abstract
MABLE investigated the efficacy and safety of rituximab plus bendamustine or rituximab plus chlorambucil in fludarabine-ineligible patients with chronic lymphocytic leukemia. Patients received rituximab plus bendamustine or rituximab plus chlorambucil every four weeks for six cycles. Rituximab plus chlorambucil-treated patients without a complete response after Cycle 6 received chlorambucil monotherapy for at least six additional cycles or until complete response. The primary endpoint was complete response rate (confirmed by bone marrow biopsy) after Cycle 6 in first-line patients. Secondary endpoints included progression-free survival, overall survival, minimal residual disease, and safety. Overall, 357 patients were randomized (rituximab plus bendamustine, n=178; rituximab plus chlorambucil, n=179; intent-to-treat population), including 241 first-line patients (n=121 and n=120, respectively); 355 patients received treatment (n=177 and n=178, respectively; safety population). In first-line patients, complete response rate after Cycle 6 (rituximab plus bendamustine, 24%; rituximab plus chlorambucil, 9%; P=0.002) and median progression-free survival (rituximab plus bendamustine, 40 months; rituximab plus chlorambucil, 30 months; P=0.003) were higher with rituximab plus bendamustine than rituximab plus chlorambucil. Overall response rate and overall survival were not different. In first-line patients with a complete response, minimal residual disease-negativity was higher with rituximab plus bendamustine than rituximab plus chlorambucil (66% vs 36%). Overall adverse event incidence was similar (rituximab plus bendamustine, 98%; rituximab plus chlorambucil, 97%). Rituximab plus bendamustine may be a valuable first-line option for fludarabine-ineligible patients with chronic lymphocytic leukemia.

PMID: 29419437 [PubMed - indexed for MEDLINE]

Telomere length regulators are activated in young men after pediatric kidney transplantation compared to healthy controls and survivors of childhood cancer-A cross-sectional study.

La, 13/07/2019 - 23:20

Telomere length regulators are activated in young men after pediatric kidney transplantation compared to healthy controls and survivors of childhood cancer-A cross-sectional study.

Pediatr Transplant. 2019 Jul 11;:e13550

Authors: Endén K, Tainio J, Hou M, Suominen A, Pakarinen M, Huang T, Söder O, Jalanko H, Jahnukainen K, Jahnukainen T

Abstract
Chronic diseases are known to cause premature aging and frailty. Data about telomere length and telomere length-regulating proteins after pediatric KTx are scarce. Leukocyte telomere length and gene expression level of eight telomere-binding proteins were analyzed in 20 KTx recipients, eight childhood NBL survivors, and nine healthy controls. The influence of key clinical parameters on telomere length and on regulators of telomere length was evaluated. The telomere length in the KTx recipients tended to be shorter (0.53 AU) than in the healthy controls (0.64 AU) but longer than in the NBL survivors (0.38 AU). There was no significant difference in telomere length between the NBL survivors and the KTx recipients (P = .110). The gene expression level of telomere length-preserving protein RPA1 was significantly higher in the KTx recipients than among the NBL survivors or healthy controls, while the expression of TRF2 and the tumor suppressor gene p16 was significantly higher in the KTX recipients when compared to the controls. TRF2 and TIN2 correlated significantly with hsCRP; additionally, TRF2 showed significant correlation with plasma creatinine and eGFR. KTx recipients have near to normal telomere length, but they have significantly higher gene expression levels of telomere regulatory proteins compared with healthy controls, suggesting activation of mechanisms preserving telomere length among KTx recipients. Our results suggest that declined graft function and consequent inflammatory response may have influence on telomerase activity.

PMID: 31297925 [PubMed - as supplied by publisher]

Phenotype-based drug screening reveals association between venetoclax response and differentiation stage in acute myeloid leukemia.

La, 13/07/2019 - 23:20

Phenotype-based drug screening reveals association between venetoclax response and differentiation stage in acute myeloid leukemia.

Haematologica. 2019 Jul 11;:

Authors: Kuusanmäki H, Leppä AM, Pölönen P, Kontro M, Dufva O, Deb D, Yadav B, Brück O, Kumar A, Everaus H, Gjertsen BT, Heinäniemi M, Porkka K, Mustjoki S, Heckman CA

Abstract
Ex vivo drug testing is a promising approach to identify novel treatment strategies for acute myeloid leukemia. However, accurate blast-specific drug responses cannot be measured with homogeneous "add-mix-measure" cell viability assays. In this study, we implemented a flow cytometry-based approach to simultaneously evaluate the ex vivo sensitivity of different cell populations in 34 primary acute myeloid leukemia samples to seven drugs and 27 rational drug combinations. Our data demonstrate that different cell populations present in acute myeloid leukemia samples have distinct sensitivity to targeted therapies. Particularly, blast cells of FAB M0/1 acute myeloid leukemia showed high sensitivity to venetoclax. In contrast, differentiated monocytic cells abundantly present in M4/5 subtypes showed resistance to Bcl-2 inhibition, whereas immature blasts in the same samples were sensitive, highlighting the importance of blast-specific readouts. Accordingly, in the total mononuclear cell fraction the highest BCL2/MCL1 gene expression ratio was observed in M0/1 and the lowest in M4/5 acute myeloid leukemia. Of the seven tested drugs, venetoclax had the highest blast-specific toxicity, and combining venetoclax with either MEK inhibitor trametinib or JAK inhibitor ruxolitinib effectively targeted all venetoclax-resistant blasts. In conclusion, we show that ex vivo efficacy of targeted agents and particularly Bcl-2 inhibitor venetoclax is influenced by the cell type, and accurate blast-specific drug responses can be assessed with a flow cytometry-based approach.

PMID: 31296572 [PubMed - as supplied by publisher]

Consensus criteria for diagnosis, staging, and treatment response assessment of T-cell prolymphocytic leukemia (T-PLL).

Pe, 12/07/2019 - 23:19

Consensus criteria for diagnosis, staging, and treatment response assessment of T-cell prolymphocytic leukemia (T-PLL).

Blood. 2019 Jul 10;:

Authors: Staber PB, Herling M, Bellido M, Jacobsen ED, Davids MS, Kadia TM, Shustov A, Tournilhac O, Bachy E, Zaja F, Porkka K, Hoermann G, Simonitsch I, Haferlach C, Kubicek S, Mayerhoefer M, Hopfinger G, Jaeger U, Dearden C

Abstract
T-cell prolymphocytic leukemia (T-PLL) is a rare, mature T-cell neoplasm with a heterogeneous clinical course. With the advent of novel treatment options that will potentially change the management of T-PLL patients it has become necessary to produce consensus guidelines for the design and conduct of clinical trials. The T-PLL International Study group (TPLL-ISG)set out to define standardized criteria for diagnosis, treatment indication, and evaluation of response. These criteria will facilitate comparison of results from clinical trials in T-PLL and will thus support clinical decision making as well as the approval of new therapeutics by healthcare authorities.

PMID: 31292114 [PubMed - as supplied by publisher]

Completeness of pediatric cancer registration in the Finnish Cancer Registry.

To, 11/07/2019 - 23:19

Completeness of pediatric cancer registration in the Finnish Cancer Registry.

Acta Oncol. 2019 Jul 10;:1-4

Authors: Jokela M, Leinonen MK, Malila N, Taskinen M, Madanat-Harjuoja LM

PMID: 31290361 [PubMed - as supplied by publisher]

Suicides and deaths linked to risky health behavior in childhood cancer patients: A Nordic population-based register study.

Ke, 10/07/2019 - 23:19

Suicides and deaths linked to risky health behavior in childhood cancer patients: A Nordic population-based register study.

Cancer. 2019 Jul 09;:

Authors: Korhonen LM, Taskinen M, Rantanen M, Erdmann F, Winther JF, Bautz A, Feychting M, Mogensen H, Talbäck M, Malila N, Ryynänen H, Madanat-Harjuoja L

Abstract
BACKGROUND: Childhood cancer survivors have been reported to be vulnerable to psychiatric morbidities and risky health behavior. Suicides, substance abuse, accidents, and violence as causes of death can be regarded as an extreme manifestation of risky health behavior. In the current study, the authors studied the risk of suicide and other risky health behavior-related deaths among childhood cancer patients in Denmark, Finland, and Sweden.
METHODS: Using linkage between national cancer, population, and cause-of-death registries, the authors investigated the causes of death in 29,285 patients diagnosed with cancer before age 20 years between 1971 and 2009 compared with a cohort of 146,282 age-matched, sex-matched, and country-matched population comparisons. Rate ratios (RRs) with 95% CIs were estimated using Poisson regression models, adjusting for demographic factors.
RESULTS: The overall risk of dying of a risky health behavior was found to be increased among childhood cancer patients (RR, 1.25; 95% CI, 1.06-1.47) when compared with population comparisons. The elevated risk was statistically significant among patients with central nervous system tumors (RR, 1.49; 95% CI, 1.08-2.05) and patients diagnosed at ages 5 to 9 years and 15 to 19 years (RR, 1.50 [95% CI, 1.01-2.24] and RR, 1.31 [95% CI, 1.03-1.67], respectively). The overall risk of suicide was found to be increased (RR, 1.37; 95% CI, 1.02-1.83), and statistically significantly so when patients were diagnosed between ages 15 and 19 years (RR, 1.61; 95% CI, 1.09-2.39).
CONCLUSIONS: Childhood cancer patients appear to have an increased risk of risky health behavior-related causes of death compared with the general population. The results of the current study suggest the importance of integrating psychosocial support into the follow-up care of these individuals.

PMID: 31287570 [PubMed - as supplied by publisher]

Myeloablative and Reduced-intensity conditioned Allogeneic Haematopoietic Stem Cell Transplantation in Myelofibrosis: A Retrospective Study by the Chronic Malignancies Working Party of EBMT.

Ke, 10/07/2019 - 23:19
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Myeloablative and Reduced-intensity conditioned Allogeneic Haematopoietic Stem Cell Transplantation in Myelofibrosis: A Retrospective Study by the Chronic Malignancies Working Party of EBMT.

Biol Blood Marrow Transplant. 2019 Jul 05;:

Authors: McLornan D, Szydlo R, Koster L, Chalandon Y, Robin M, Wolschke C, Beelen D, Socié G, Bornhäuser M, Angelucci E, Niederwieser D, Gerbitz A, Finke J, Vitek A, Itälä-Remes M, Radujkovic A, Kanz L, Potter V, Chevallier P, Stelljes M, Petersen E, Robinson S, Poiré X, Klyuchnikov E, Hernández-Boluda JC, Czerw T, Hayden P, Kröger N, Yakoub-Agha I

Abstract
This retrospective study by the EBMT analysed the outcome of 2224 Myelofibrosis patients who underwent allogeneic stem cell transplantation (allo-SCT) between 2000-2014; 781 (35%) underwent myeloablative conditioning (MAC) and 1443 (65%) reduced intensity conditioning (RIC). Median patient age was 52.9 years (r, 18-74) and 57.5 years (range(r), 21-76) in the MAC and RIC cohorts respectively. Donor type was similar: matched sibling donors (MAC- 317 (41%)) and RIC- 552 (38%) and unrelated donors (UD; MAC (464 (59%); RIC- 891 (62%)). Median time to both neutrophil and platelet (>20 × 109/L) engraftment did not differ between cohorts. Rates of grade II-IV acute (a) GVHD were 28% (MAC) and 31% (RIC; (p=ns). Cumulative cGVHD rates (limited/ extensive) were 22%/27% (MAC) and 19%/ 31% (RIC; p=0.10). Cumulative incidences of Non-relapse mortality (NRM) at 1, 3 and 5-years were: 25.5%, 32.2% and 34.6% (MAC) and 26.3%, 32.8% and 34.4% (RIC). There was a trend towards a higher relapse rate with RIC regimens compared to MAC (p=0.08); rates at 1, 3 and 5-years were: 10.9%, 17.2% and 20.1% (MAC) and 14%, 19.7% and 23.2% (RIC), respectively. No significant difference in 5yr probabilities of overall survival (OS) was noted: MAC 53.0% (95% confidence intervals (CI) 49.1-56.9) and RIC 51.0% (95% CI: 48.3-53.7); p=0.78. Regarding the composite end point of GVHD-free/relapse-free survival (GRFS), the unadjusted Kaplan-Meier estimate of 5-year GRFS was 32.4% (95% CI: 29.0-36.1) in the MAC group and 26.1% (95% CI: 23.9-28.2) in the RIC group (p=0.001). In the MAC cohort, multivariable analysis confirmed worse OS and NRM with older age (>50 yrs), using an unrelated donor and a Karnofsky Performance Status (KPS) of 80 or less. For the RIC cohort, worse OS and NRM was associated with age 60- 70 years when compared to younger recipients, use of a mismatched donor and poor performance status. In conclusion, although similar OS rates existed for both cohorts overall, this study suggests that MAC should still be used for younger individuals suitable for such an approach due to a trend towards less relapse and an overall suggested advantage of improved GRFS; albeit this should be examined in a more homogeneous cohort. RIC allo-SCT still offers significant survival advantage in the older, fitter MF allograft patient and optimisation to reduce significant relapse and NRM rates are required.

PMID: 31284069 [PubMed - as supplied by publisher]

A catalog of genetic loci associated with kidney function from analyses of a million individuals.

Ke, 10/07/2019 - 23:19
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A catalog of genetic loci associated with kidney function from analyses of a million individuals.

Nat Genet. 2019 06;51(6):957-972

Authors: Wuttke M, Li Y, Li M, Sieber KB, Feitosa MF, Gorski M, Tin A, Wang L, Chu AY, Hoppmann A, Kirsten H, Giri A, Chai JF, Sveinbjornsson G, Tayo BO, Nutile T, Fuchsberger C, Marten J, Cocca M, Ghasemi S, Xu Y, Horn K, Noce D, van der Most PJ, Sedaghat S, Yu Z, Akiyama M, Afaq S, Ahluwalia TS, Almgren P, Amin N, Ärnlöv J, Bakker SJL, Bansal N, Baptista D, Bergmann S, Biggs ML, Biino G, Boehnke M, Boerwinkle E, Boissel M, Bottinger EP, Boutin TS, Brenner H, Brumat M, Burkhardt R, Butterworth AS, Campana E, Campbell A, Campbell H, Canouil M, Carroll RJ, Catamo E, Chambers JC, Chee ML, Chee ML, Chen X, Cheng CY, Cheng Y, Christensen K, Cifkova R, Ciullo M, Concas MP, Cook JP, Coresh J, Corre T, Sala CF, Cusi D, Danesh J, Daw EW, de Borst MH, De Grandi A, de Mutsert R, de Vries APJ, Degenhardt F, Delgado G, Demirkan A, Di Angelantonio E, Dittrich K, Divers J, Dorajoo R, Eckardt KU, Ehret G, Elliott P, Endlich K, Evans MK, Felix JF, Foo VHX, Franco OH, Franke A, Freedman BI, Freitag-Wolf S, Friedlander Y, Froguel P, Gansevoort RT, Gao H, Gasparini P, Gaziano JM, Giedraitis V, Gieger C, Girotto G, Giulianini F, Gögele M, Gordon SD, Gudbjartsson DF, Gudnason V, Haller T, Hamet P, Harris TB, Hartman CA, Hayward C, Hellwege JN, Heng CK, Hicks AA, Hofer E, Huang W, Hutri-Kähönen N, Hwang SJ, Ikram MA, Indridason OS, Ingelsson E, Ising M, Jaddoe VWV, Jakobsdottir J, Jonas JB, Joshi PK, Josyula NS, Jung B, Kähönen M, Kamatani Y, Kammerer CM, Kanai M, Kastarinen M, Kerr SM, Khor CC, Kiess W, Kleber ME, Koenig W, Kooner JS, Körner A, Kovacs P, Kraja AT, Krajcoviechova A, Kramer H, Krämer BK, Kronenberg F, Kubo M, Kühnel B, Kuokkanen M, Kuusisto J, La Bianca M, Laakso M, Lange LA, Langefeld CD, Lee JJ, Lehne B, Lehtimäki T, Lieb W, Lifelines Cohort Study, Lim SC, Lind L, Lindgren CM, Liu J, Liu J, Loeffler M, Loos RJF, Lucae S, Lukas MA, Lyytikäinen LP, Mägi R, Magnusson PKE, Mahajan A, Martin NG, Martins J, März W, Mascalzoni D, Matsuda K, Meisinger C, Meitinger T, Melander O, Metspalu A, Mikaelsdottir EK, Milaneschi Y, Miliku K, Mishra PP, V. A. Million Veteran Program, Mohlke KL, Mononen N, Montgomery GW, Mook-Kanamori DO, Mychaleckyj JC, Nadkarni GN, Nalls MA, Nauck M, Nikus K, Ning B, Nolte IM, Noordam R, O'Connell J, O'Donoghue ML, Olafsson I, Oldehinkel AJ, Orho-Melander M, Ouwehand WH, Padmanabhan S, Palmer ND, Palsson R, Penninx BWJH, Perls T, Perola M, Pirastu M, Pirastu N, Pistis G, Podgornaia AI, Polasek O, Ponte B, Porteous DJ, Poulain T, Pramstaller PP, Preuss MH, Prins BP, Province MA, Rabelink TJ, Raffield LM, Raitakari OT, Reilly DF, Rettig R, Rheinberger M, Rice KM, Ridker PM, Rivadeneira F, Rizzi F, Roberts DJ, Robino A, Rossing P, Rudan I, Rueedi R, Ruggiero D, Ryan KA, Saba Y, Sabanayagam C, Salomaa V, Salvi E, Saum KU, Schmidt H, Schmidt R, Schöttker B, Schulz CA, Schupf N, Shaffer CM, Shi Y, Smith AV, Smith BH, Soranzo N, Spracklen CN, Strauch K, Stringham HM, Stumvoll M, Svensson PO, Szymczak S, Tai ES, Tajuddin SM, Tan NYQ, Taylor KD, Teren A, Tham YC, Thiery J, Thio CHL, Thomsen H, Thorleifsson G, Toniolo D, Tönjes A, Tremblay J, Tzoulaki I, Uitterlinden AG, Vaccargiu S, van Dam RM, van der Harst P, van Duijn CM, Velez Edward DR, Verweij N, Vogelezang S, Völker U, Vollenweider P, Waeber G, Waldenberger M, Wallentin L, Wang YX, Wang C, Waterworth DM, Bin Wei W, White H, Whitfield JB, Wild SH, Wilson JF, Wojczynski MK, Wong C, Wong TY, Xu L, Yang Q, Yasuda M, Yerges-Armstrong LM, Zhang W, Zonderman AB, Rotter JI, Bochud M, Psaty BM, Vitart V, Wilson JG, Dehghan A, Parsa A, Chasman DI, Ho K, Morris AP, Devuyst O, Akilesh S, Pendergrass SA, Sim X, Böger CA, Okada Y, Edwards TL, Snieder H, Stefansson K, Hung AM, Heid IM, Scholz M, Teumer A, Köttgen A, Pattaro C

Abstract
Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through trans-ancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these, 147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.

PMID: 31152163 [PubMed - indexed for MEDLINE]

ACTN1 mutations lead to a benign form of platelet macrocytosis not always associated with thrombocytopenia.

Ke, 10/07/2019 - 23:19
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ACTN1 mutations lead to a benign form of platelet macrocytosis not always associated with thrombocytopenia.

Br J Haematol. 2018 10;183(2):276-288

Authors: Faleschini M, Melazzini F, Marconi C, Giangregorio T, Pippucci T, Cigalini E, Pecci A, Bottega R, Ramenghi U, Siitonen T, Seri M, Pastore A, Savoia A, Noris P

Abstract
The inherited thrombocytopenias (IT) are a heterogeneous group of diseases resulting from mutations in more than 30 different genes. Among them, ACTN1-related thrombocytopenia (ACTN1-RT; Online Mendelian Inheritance in Man: 615193) is one of the most recently identified forms. It has been described as a mild autosomal dominant macrothrombocytopenia caused by mutations in ACTN1, a gene encoding for one of the two non-muscle isoforms of α-actinin. We recently identified seven new unrelated families with ACTN1-RT caused by different mutations. Two of them are novel missense variants (p.Trp128Cys and p.Pro233Leu), whose pathogenic role has been confirmed by in vitro studies. Together with the 10 families we have previously described, our cohort of ACTN1-RT now consists of 49 individuals carrying ACTN1 mutations. This is the largest case series ever collected and enabled a critical evaluation of the clinical aspects of the disease. We concluded that ACTN1-RT is the fourth most frequent form of IT worldwide and it is characterized by platelet macrocytosis in all affected subjects and mild thrombocytopenia in less than 80% of cases. The risk of bleeding, either spontaneous or upon haemostatic challenge, is negligible and there are no other associated defects, either congenital or acquired. Therefore, ACTN1-RT is a benign form of IT, whose diagnosis provides affected individuals and their families with a good prognosis.

PMID: 30351444 [PubMed - indexed for MEDLINE]

Measurable residual disease, conditioning regimen intensity, and age predict outcome of allogeneic hematopoietic cell transplantation for acute myeloid leukemia in first remission: A registry analysis of 2292 patients by the Acute Leukemia Working...

Ke, 10/07/2019 - 23:19
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Measurable residual disease, conditioning regimen intensity, and age predict outcome of allogeneic hematopoietic cell transplantation for acute myeloid leukemia in first remission: A registry analysis of 2292 patients by the Acute Leukemia Working Party European Society of Blood and Marrow Transplantation.

Am J Hematol. 2018 09;93(9):1142-1152

Authors: Gilleece MH, Labopin M, Yakoub-Agha I, Volin L, Socié G, Ljungman P, Huynh A, Deconinck E, Wu D, Bourhis JH, Cahn JY, Polge E, Mohty M, Savani BN, Nagler A

Abstract
Patients with acute myeloid leukemia (AML) in morphological first complete remission (CR1) pre-allogeneic hematopoietic cell transplantation (HCT) may have measurable residual disease (MRD) by molecular and immunophenotyping criteria. We assessed interactions of MRD status with HCT conditioning regimen intensity in patients aged <50 years (y) or ≥50y. This was a retrospective study by the European Society for Blood and Marrow Transplantation registry. Patients were >18y with AML CR1 MRD NEG/POS and recipients of HCT in 2000-2015. Conditioning regimens were myeloablative (MAC), reduced intensity (RIC) or non-myeloablative (NMA). Outcomes included leukemia free survival (LFS), overall survival (OS), relapse incidence (RI), non-relapse mortality (NRM), chronic graft-vs-host (cGVHD), and GVHD-free and relapse-free survival (GRFS). The 2292 eligible patients were categorized into four paired groups: <50y MRD POS MAC (N = 240) vs RIC/NMA (N = 58); <50y MRD NEG MAC (N = 665) vs RIC/NMA (N = 195); ≥50y MRD POS MAC (N = 126) vs RIC/NMA (N = 230), and ≥50y MRD NEG MAC (N = 223) vs RIC/NMA (N = 555). In multivariate analysis RIC/NMA was only inferior to MAC for patients in the <50y MRD POS group, with worse RI (HR 1.71) and LFS (HR 1.554). Patients <50Y MRD NEG had less cGVHD after RIC/NMA HCT (HR 0.714). GRFS was not significantly affected by conditioning intensity in any group. Patients aged <50y with AML CR1 MRD POS status should preferentially be offered MAC allo-HCT. Prospective studies are needed to address whether patients with AML CR1 MRD NEG may be spared the toxicity of MAC regimens. New approaches are needed for ≥50y AML CR1 MRD POS.

PMID: 29981272 [PubMed - indexed for MEDLINE]

Impact of extramedullary disease in patients with newly diagnosed multiple myeloma undergoing autologous stem cell transplantation: a study from the Chronic Malignancies Working Party of the EBMT.

Ke, 10/07/2019 - 23:19
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Impact of extramedullary disease in patients with newly diagnosed multiple myeloma undergoing autologous stem cell transplantation: a study from the Chronic Malignancies Working Party of the EBMT.

Haematologica. 2018 05;103(5):890-897

Authors: Gagelmann N, Eikema DJ, Iacobelli S, Koster L, Nahi H, Stoppa AM, Masszi T, Caillot D, Lenhoff S, Udvardy M, Crawley C, Arcese W, Mariette C, Hunter A, Leleu X, Schipperus M, Delforge M, Pioltelli P, Snowden JA, Itälä-Remes M, Musso M, van Biezen A, Garderet L, Kröger N

Abstract
We investigated extramedullary disease in newly diagnosed multiple myeloma patients and its impact on outcome following first-line autologous stem cell transplantation. We identified 3744 adult myeloma patients who received up-front single (n=3391) or tandem transplantation (n=353) between 2005 and 2014 with available data on extramedullary involvement at diagnosis. The overall incidence of extramedullary disease was 18.2% (n=682) and increased per year from 6.5% (2005) to 23.7% (2014). Paraskeletal involvement was found in 543 (14.5%) and extramedullary organ involvement in 139 (3.7%). More patients with extramedullary organ involvement had multiple involved sites (≥2; P<0.001). In a comparison of patients with single sites with patients without the disease, up-front transplantation resulted in at least similar 3-year progression-free survival (paraskeletal: P=0.86, and extramedullary organ: P=0.88). In single paraskeletal involvement, this translated less clearly into worse 3-year overall survival (P=0.07) while single organ involvement was significantly worse (P=0.001). Multiple organ sites were associated with worse outcome (P<0.001 and P=0.01). First-line treatment with tandem compared with single transplantation resulted in similar survival in patients with extramedullary disease at diagnosis (P=0.13 for both).

PMID: 29419433 [PubMed - indexed for MEDLINE]

Allogeneic stem cell transplantation for blast crisis chronic myeloid leukemia in the era of tyrosine kinase inhibitors - A retrospective study by the EBMT Chronic Malignancies Working Party.

Pe, 05/07/2019 - 23:16
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Allogeneic stem cell transplantation for blast crisis chronic myeloid leukemia in the era of tyrosine kinase inhibitors - A retrospective study by the EBMT Chronic Malignancies Working Party.

Biol Blood Marrow Transplant. 2019 Jul 01;:

Authors: Radujkovic A, Dietrich S, Blok HJ, Nagler A, Ayuk F, Finke J, Tischer J, Mayer J, Koc Y, Sorà F, Passweg J, Byrne JL, Jindra P, Veelken JH, Socié G, Maertens J, Schaap N, Stadler M, Itälä-Remes M, Tholouli E, Arat M, Rocha V, Ljungman P, Yakoub-Agha I, Kröger N, Chalandon Y

Abstract
The prognosis of patients with blast crisis (BC) chronic myeloid leukemia (CML) is still dismal. Allogeneic stem cell transplantation (alloSCT) represents the only curative treatment option, but data on transplant outcomes are scarce. We therefore conducted a retrospective, registry based study of adult patients allografted for BC CML focusing on patients with active disease at transplant and pre-transplant prognostic factors. A total of 170 patients allografted for BC CML after tyrosine kinase inhibitor pre-treatment between 2004 and 2016 were analyzed. Prior to transplant, 95 patients were in remission, whereas 75 patients had active BC. In multivariable analysis of the entire cohort, active BC at transplant was the strongest factor associated with decreased overall survival (OS, HR 1.87, P=0.010) and shorter leukemia-free survival (LFS, HR 1.69, P=0.017). For patients with BC in remission at transplant, advanced age (≥45 years), lower performance status (≤80%), longer interval from diagnosis BC to transplant (>12 months), myeloablative conditioning, and unrelated donor (UD) transplant were risk factors for inferior survival. In patients with active BC, only UD transplant was significantly associated with prolonged LFS and trended towards improved OS. In summary, survival of patients allografted for BC CML was strongly dependent on the pre-transplant remission status. In patients with remission of BC, conventional prognostic factors remained the major determinants of outcome, whereas in those with active BC at transplant, UD transplantation was associated with prolonged LFS in our study.

PMID: 31271884 [PubMed - as supplied by publisher]

Post-Transplant Cyclophosphamide versus Antithymocyte Globulin in HLA-Mismatched unrelated Donors transplantation.

Pe, 05/07/2019 - 23:16
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Post-Transplant Cyclophosphamide versus Antithymocyte Globulin in HLA-Mismatched unrelated Donors transplantation.

Blood. 2019 Jul 03;:

Authors: Battipaglia G, Labopin M, Kröger N, Vitek A, Afanasyev B, Hilgendorf I, Schetelig J, Ganser A, Blaise D, Itälä-Remes M, Passweg JR, Bonifazi F, Finke J, Ruggeri A, Nagler A, Mohty M

Abstract
The use of antithymocyte globulin (ATG) has represented the standard of care in graft-versus-host (GVHD) prophylaxis in patients undergoing mismatched unrelated donor (MMUD) transplant. The safety and feasibility of post-transplant cyclophosphamide (PTCY) in this setting has recently been reported, but no studies have compared to date the outcomes of PTCY versus ATG in a 9/10 MMUD transplant. Using the registry data of the ALWP of the EBMT we performed a matched-pair analysis comparing those two strategies in a 9/10 MMUD setting. Ninety-three patients receiving PTCY were matched with 179 patients receiving ATG. A significantly lower incidence of severe acute GVHD was observed with PTCY as compared to ATG. Recipients of the former also showed higher leukemia-free and GVHD/relapse-free survival (GRFS). When performing a subgroup analysis including patients receiving peripheral blood stem cells, or being in complete remission (CR), or receiving the same associated immunosuppressive agents, superiority of PTCY over ATG was confirmed. Similarly to the haploidentical setting, use of PTCY is an effective anti GVHD prophylaxis also in the 9/10 MMUD transplant. Use of PTCY may also provide better outcomes in long-term disease control. These results need confirmation in large prospective randomized trials.

PMID: 31270102 [PubMed - as supplied by publisher]

Risk of secondary haematological malignancies in patients with follicular lymphoma: an analysis of 1028 patients treated in the rituximab era.

To, 04/07/2019 - 23:16
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Risk of secondary haematological malignancies in patients with follicular lymphoma: an analysis of 1028 patients treated in the rituximab era.

Br J Haematol. 2019 Jul 03;:

Authors: Prusila REI, Sorigue M, Jauhiainen J, Mercadal S, Postila A, Salmi P, Tanhua T, Tikkanen S, Kakko S, Kuitunen H, Pollari M, Nystrand I, Kuusisto MEL, Vasala K, Jantunen E, Korkeila E, Karihtala P, Sancho JM, Turpeenniemi-Hujanen T, Kuittinen O

Abstract
Follicular lymphoma (FL) is the most common indolent lymphoma. Currently there are many comparable treatment options available for FL. When selecting the most optimal therapy it is important to consider possible late effects of the treatment as well as survival. Secondary haematological malignancy (SHM) is a severe late effect of treatments, but the incidence of SHMs is still largely unknown. The goal of the present study was to determine the incidence of SHMs and how therapeutic decisions interfere with this risk. The study included 1028 FL patients with a median follow-up time of 5·6 years. The 5-year risk of SHM was 1·1% and the risk was associated with multiple lines of treatment (P = 0·016). The 5-year risk of SHM was 0·5% after the first-line treatment and 1·6% after the second-line. The standardized incidence ratio (SIR) was 6·2 (95% confidence interval 3·4-10·5) for SHM overall. This retrospective study found that the risk of SHM was low after first-line treatment in FL patients from the rituximab era. However, the risk of SHM increases with multiple lines of treatment. Therapeutic approaches should aim to achieve as long a remission as possible with first-line treatment, thereby postponing the added risk of SHM.

PMID: 31267514 [PubMed - as supplied by publisher]