Hepatic complications of allogeneic hematopoietic cell transplantation

Hepatic complications of allogeneic hematopoietic cell transplantation contribute substantially to the overall success of the procedure and represent a major cause of morbidity and mortality. Early hepatic complications consist of the sinusoidal obstruction syndrome, drug toxicities, infections, and acute graft-versus-host disease, while late hepatic complications consist of chronic graft-versus host disease, chronic viral hepatitis, and iron overload states. Successful management of the hepatic complications of allogeneic hematopoietic cell transplantation is dependent on several factors. These include the recognition and elimination of any pre-transplant risk factors for these problems and the development of strategies to evaluate and prevent them in both the early and later post-transplant periods. The aims of the present review are 1) to identify the early and late hepatic complications of allogeneic hematopoietic cell transplantation, in the chronological order in which they occur, 2) to characterize the diagnostic procedures used to identify them, and finally 3) to present the current therapeutic approaches used to manage these problems

Türkiye akademik CAR-T hücre (ISIKOK-19) klinik çalışması ön raporu: Ürün karakterizasyonu ve klinik uygulama sonuçları

Objective: Chimeric antigen receptor T (CAR-T) cell therapies have already made an impact on the treatment of B-cell malignancies. Although CAR-T cell therapies are promising, there are concerns about commercial products regarding their affordability and sustainability. In this preliminary study, the results of the first production and clinical data of an academic CAR-T cell (ISIKOK-19) trial in Turkey are presented. Materials and Methods: A pilot clinical trial (NCT04206943) designed to assess the safety and feasibility of ISIKOK-19 T-cell therapy for patients with relapsed and refractory CD19+ tumors was conducted and participating patients received ISIKOK-19 infusions between October 2019 and July 2021. The production data of the first 8 patients and the clinical outcome of 7 patients who received ISIKOK-19 cell infusions are presented in this study. Results: Nine patients were enrolled in the trial [5 with acute lymphoblastic leukemia (ALL) and 4 with non-Hodgkin lymphoma (NHL)], but only 7 patients could receive treatment. Two of the 3 participating ALL patients and 3 of the 4 NHL patients had complete/ partial response (overall response rate: 72%). Four patients (57%) had CAR-T-related toxicities (cytokine release syndrome, CAR-T-related encephalopathy syndrome, and pancytopenia). Two patients were unresponsive and had progressive disease following CAR-T therapy. Two patients with partial response had progressive disease during follow-up. Conclusion: Production efficacy and fulfillment of the criteria of quality control were satisfactory for academic production. Response rates and toxicity profiles were also acceptable for this heavily pretreated/refractory patient group. ISIKOK-19 cells appear to be a safe, economical, and efficient treatment option for CD19+ tumors. However, the findings of this study need to be supported by the currently ongoing ISIKOK-19 clinical trial.Amaç: Kimerik antijen reseptör T (CAR-T) hücre uygulamaları B-hücreli malignitelerin tedavisinde etkili olmaktadır. CAR-T hücre uygulamalarının sonuçları umut vaadedici olsa da, ticari CAR-T ürünlerinin yükek maliyetleri nedeniyle ulaşılabilirlik açısından ciddi sorunlar yaşanmaktadır. Bu ön raporda, Türkiye’deki ilk akademik CAR-T hücre çalışmasının üretim ve klinik uygulama sonuçları sunulmuştur. Gereç ve Yöntemler: Relaps refrakter CD 19+ hematolojik maligniteli hastalarda ISIKOK-19 T-hücre tedavisinin güvenliği ve etkinliğini değerlendirmek amacıyla yürütülen klinik çalışmaya (NCT04206943) Ekim 2019-Temmuz 2021 tarihleri arasındaki hastalar dahil edilmiştir. Bu raporda ilk 8 hastanın üretim bilgileriyle, ISIKOK-19 hücre infüzyonu yapılan 7 hastanın klinik sonuçları sunulmuştur. Bulgular: Çalışmaya toplam 9 hasta dahil edilmiştir (5 akut lenfoblastik lösemi [ALL] ve 4 non-hodgkin lenfoma [NHL]), ancak sadece 7 hastaya hücre infüzyonu yapılabilmiştir. Hücre infüzyonu alan 3 ALL hastasından 2’sinde ve 4 NHL hastasının 3’ünde tam/kısmi cevap gözlenmiştir (toplam yanıt oranı %72). Dört hastada (%57) CAR-T ilişkili toksisite (sitokin salınım sendromu, immün efektör hücre ilişkili nörotoksisite sendromu ve pansitopeni) tespit edilmiştir. İki hastada ise CAR-T hücre uygulaması sonrası cevapsızlık ve progresif hastalık izlenmiştir. Kısmi cevap veren hastalardan 2’sinde de takip sırasında progresif hastalık tespit edilmiştir. Sonuç: Akademik CAR-T üretimimiz, üretim etkinliği ve kalite kontrol kriterlerinin tam olarak karşılanması açısından tatmin edici sonuçlara sahiptir. Çalışmaya dahil edilen hastaların tedavi yükü hesaba katıldığında tedaviye cevap oranı ve toksisite profili açısından da sonuçlar kabul edilebilir düzeydedir. Bu sonuçlarla, ISIKOK-19 hücrelerinin güvenli, ekonomik ve etkili bir tedavi seçeneği olduğu düşünülebilir. Ancak bu ön sonuçların halen devam eden ISIKOK-19 klinik çalışmasıyla desteklenmesi beklenmektedir

Reduced 8-Gray compared to standard 12-Gray Total Body Irradiation for allogeneic transplantation in first remission acute lymphoblastic leukemia: a study of the Acute Leukemia Working Party of the EBMT

In this registry-based study, we compared outcomes of allogeneic hematopoietic cell transplantation (allo-HCT) in adult patients with acute lymphoblastic leukemia (ALL) transplanted in first complete remission (CR-1), following conditioning with total body irradiation (TBI) at a standard 12-Gray or at a lower 8-Gray total dose. Patients received fludarabine (flu) as the sole chemotherapy complementing TBI. Eight-Gray TBI/flu was used in 494 patients and 12-Gray TBI/flu in 145 patients. Eighty-eight (23.1%) and 36 (29%) of the patients had Ph-negative B-ALL, 222 (58.3%) and 53 (42.7%) had Ph-positive B-ALL, 71 (18.6%) and 35 (28.2%) T-ALL, respectively (P = 0.008). Patients treated with 8-Gray were older than ones received 12-Gray (median 55.7 versus 40.3 years, P < 0.0001) and were more frequently administered in vivo T-cell depletion (71% versus 40%, P <0.0001). In a multivariate model adjusted for age, type of ALL, and other prognostic factors, leukemia-free survival (primary endpoint) as well as relapse, nonrelapse mortality, overall survival, and GVHD-free, relapse-free survival were not influenced by the TBI dose. These results were confirmed when we focused on patients <55 years of age (median 47 years). Patients with Ph-positive ALL or T-ALL had significantly better survival outcomes than ones with Ph-negative B-ALL, mainly due to significantly fewer relapses. We conclude that 8-Gray TBI is sufficient for adult patients with ALL transplanted in CR-1 with no additional benefit of augmenting the conditioning intensity to 12-Gray

Outcome of Allogeneic Transplantation for Mature T-cell Lymphomas: Impact of Donor Source and Disease Characteristics

Mature T-cell lymphomas constitute the most common indication for allogeneic hematopoietic cell transplantation (allo-HCT) of all lymphomas. Large studies evaluating contemporary outcomes of allo-HCT in mature T-cell lymphomas relative to commonly used donor sources are not available. Included in this registry study were adult patients who had undergone allo-HCT for anaplastic large cell lymphoma, angioimmunoblastic T-cell lymphoma (AITL), or peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) between 2008 and 2018. Hematopoietic cell transplantation (HCT) platforms compared were posttransplant cyclophosphamidebased haploidentical (haplo-)HCT, matched sibling donor (MSD) HCT, matched unrelated donor HCT with in vivo T-cell depletion (MUD TCD+), and matched unrelated donor HCT without in vivo T-cell depletion (MUD TCD-). Coprimary end points were overall survival (OS) and progression-free survival (PFS); secondary end points included nonrelapse mortality (NRM), and relapse/progression incidence (RI). A total of 1942 patients were eligible (237 haplo-HCT; 911 MSD; 468 MUD TCD+; 326 MUD TCD-). Cohorts were comparable for baseline characteristics with the exception of higher proportions of patients with decreased performance status (PS) and marrow graft recipients in the haplo-HCT group. Using univariate and multivariate comparisons, OS, PFS, RI, and NRM were not significantly different among the haplo-HCT, MSD, MUD TCD+, and MUD TCD- cohorts, with 3-year OS and PFS of 60%, 63%, 59%, and 64%, respectively, and 50%, 50%, 48%, and 52%, respectively. Significant predictors of inferior OS and PFS on multivariate analysis were active disease status at HCT and decreased PS. AITL was associated with significantly reduced relapse risk and better PFS compared with PTCL-NOS. Allo-HCT can provide durable PFS in patients with mature T-cell lymphoma (TCL). Outcomes of haplo-HCT were comparable to those of matched donor allo-HCT

Current incidence, severity, and management of veno-occlusive disease/sinusoidal obstruction syndrome in adult allogeneic HSCT recipients:an EBMT Transplant Complications Working Party study

The current incidence, diagnostic policy, management, and outcome of VOD/SOS at EBMT centers were studied. All centers that had performed allogeneic HSCTs in adult patients within one defined year were invited to the study. Seventy-one centers participated with a total of 2886 allogeneic transplantations and 93 cases of VOD/SOS in 2018. The cumulative incidence of VOD/SOS at day 21 was 1.8% and at day 100 2.4%. Of 67 cases with detailed data, 52 were classical and 15 (22%) late onset (&gt;day 21). According to the EBMT criteria, 65/67 patients had at least two VOD/SOS risk factors. The severity grades were: mild 0, moderate 3, severe 29, very severe 35. Fifty-four patients were treated with defibrotide. VOD/SOS resolved in 58% of the patients, 3/3 with moderate, 22/28 with severe, and 12/33 with very severe grade (p &lt; 0.001). By day 100, 57% of the patients were alive; 3/3 with moderate, 22/29 with severe, and 13/35 with very severe VOD/SOS (p = 0.002). In conclusion, the incidence of VOD/SOS was low. Severe and very severe grades dominated. Very severe grade predicted poor outcome compared to severe grade further supporting the concept of early diagnosis and treatment to avoid a dismal outcome. [Figure not available: see fulltext.]</p

Diagnosis and severity criteria for sinusoidal obstruction syndrome/veno-occlusive disease in adult patients: a refined classification from the European society for blood and marrow transplantation (EBMT).

peer reviewedSinusoidal obstruction syndrome, also known as veno-occlusive disease (SOS/VOD), is a potentially life-threatening complication that can develop after hematopoietic cell transplantation (HCT). A new definition for diagnosis, and a severity grading system for SOS/VOD in adult patients, was reported a few years ago on behalf of the European Society for Blood and Marrow Transplantation (EBMT). The aim of this work is to update knowledge regarding diagnosis and severity assessment of SOS/VOD in adult patients, and also its pathophysiology and treatment. In particular, we now propose to refine the previous classification and distinguish probable, clinical and proven SOS/VOD at diagnosis. We also provide an accurate definition of multiorgan dysfunction (MOD) for SOS/VOD severity grading based on Sequential Organ Failure Assessment (SOFA) score

Clinical use of hematopoietic stem cells

İstanbul Bilim Üniversitesi, Tıp Fakültesi.Hematopoetik kök hücreler (HKH) klinik olarak 1950’lerden beri kullanılmaktadır. Kemik iliğinin benign rahatsızlıklarında (Örn. Edinsel ağır aplastik anemi, Fankoni anemisi, Talasemi majör, Orak hücreli anemi gibi) terapötik ve malign rahatsızlıklarında postremisyon tedavi konsolidasyonu amaçlı kullanıma rutin olarak girmesi yetmişli yıllara doğru olmuştur. Yılda artık 10-80 bin HKH nakli yapılmakta olup, bir milyonuncu nakil yakın zamanda yapılmıştır. Ülkemizde yapılan işlemlerde son beş yıl içerisinde nakil merkezi sayısı ikiye katlanmış ve toplam nakil sayısı 3.000’lere ulaşmıştır. Bu evrensel ve standart tedavi yönteminin başarısı, onarım tıbbı amaçlı çalışmaların da hızlanmasına yol açmıştır. Kardiyoloji bu alanda başı çekmiş, takiben nörolojik bilimler ve karaciğer rahatsızlıklarında kemik iliği veya çevre kanı tabanlı HKH’lerin çeşitli rahatsızlıklarda deneysel amaçlı klinik kullanımının arttığı gözlenmiştir. Ülkemizde de bu konuda az sayıda klinik araştırma yapılmıştır. Bu konuda erişkin kök hücrelerin, mezenkimal kök hücreler (MKH) dışında standart kinik kullanımına ait bir gelişme yaşanmazken, MKH ve diğer erişkin ve embriyonik kök hücrelerin onarım tıbbındaki araştırmaları olanca hızıyla devam etmektedir. Ülkemizde HKH nakli yayınlanmış standart evrensel endikasyonlarda uygulanmakta ve geri ödenmekteyken, hematoloji dışı erişkin HKH’lerin kullanımı T.C. Sağlık Bakanlığı’nın yasal iznine tabidir. Diğer yandan embriyonik kök hücrelerin klinik kullanımı tamamen yasaklanmıştır. Bu derlemede standart klinik kullanım, endikasyonları, tipleri, sık komplikasyonları ile ülkemizde yürütülmüş olan HKH tabanlı onarım tıbbı yaklaşımları gözden geçirilmiştir.Hematopoietic stem cells (HSC) have been used clinically since the 1950s. Towards the seventies, they have been started to be used routinely for therapeutic purpose in benign disorders of bone marrow (e.g. acquired severe aplastic anemia, Fanconi anemia, Thalassemia major, sickle cell anemia) and for postremission treatment consolidation purpose in malign disorders of bone marrow. Currently, 10 to 80 thousand HSC transplantations are performed annually and the one millionth transplantation was performed recently. Regarding the procedures performed in our country, the number of transplantation centers doubled during the last five years and the total number of transplantations reached 3,000s. The success of this universal and standard treatment method has accelerated studies on regenerative medicine. In this respect, cardiology has led the way, followed by neurological sciences and liver disorders and it was observed that the clinical use of bone marrow or peripheral blood HSCs for experimental purpose in various disorders has increased. In our country, a limited number of clinical research has been conducted on this subject. Hereof, while there is no development involving the standard clinical use of adult stem cells except for mesenchymal stem cells (MSC), researches on MSC and other adult and embryonic stem cells in regenerative medicine are ongoing at full speed. In our country, while HSC transplantation is performed in published standard universal indications and reimbursed, usage of non-hematologic adult HSCs is subject to legal permission from Turkish Republic’s Ministry of Health. On the other hand, clinical use of embryonic stem cells is forbidden completely. In this review, we aimed to overview HSC based regenerative medicine approaches conducted in our country in terms of standard clinical use, indications, types, and frequent complications

The use of second allogeneic hematopoietic stem cell transplantation for hematologic malignancies relapsed after the first: Does it worth to do?

WOS: 000374614700017PubMed ID: 26976480Allogeneic (allo) hematopoietic stem cell transplantation (HSCT) is the only curative option for many malignant and benign hematological disorders. It seems hopeless for patients who relapse after this strategy. In the era of developing breakthrough therapies, we can hope for better, but for patients relapsed after the first allo HSCT probably the best therapy option for long term survival is still another allo HSCT. Interval between first allo HSCT and relapse of primary disease and achievement of complete response after the relapse are the most prominent factors for long time survival for patient after second all HSCT. (c) 2016 Elsevier Ltd. All rights reserved

Peripheral blood stem cell collection for allogeneic hematopoietic stern cell transplantation: Practical implications after 200 consequent transplants

WOS: 000423246100008Background: Proper stem cell mobilization is one of the most important steps in hematopoietic stem cell transplantation (HSCT). The aim of this paper is to share our 6 years' experience and provide practical clinical approaches particularly for stem cell mobilization and collection within the series of more than 200 successive allogeneic HSCT at our transplant center. Subjects & Methods: Two hundred and seven consecutive patients who underwent allogeneic peripheral blood stem cell transplantation were included in this study. Age, sex, weight, complete blood counts, CD34(+) cell counts, total collected amount of CD34(+) cells, CD34(+) cells per 101 processed, mobilization failure and adverse events were reviewed. Results: Median age was 40.2 +/- 12.9 (21-68) years and 46.4 +/- 13.4 (17-67) years for donors and patients, respectively. The number of donors who had undergone adequate CD34(+) cell harvesting and completed the procedure on the fourth day was 67 (32.8% of all patients). Only 12 patients required cell apheresis both on day 5 and 6. Apheresis was completed on day 4 and/or day 5 in 94.2% of all our donors. There was no significant association between CD34(+) stem cell volume and age, gender and weight values of donors. Mobilization failure was not seen in our series. Conclusions: G-CSF is highly effective in 1/3 of the donors on the 4th day in order to collect enough number of stem cells. We propose that peripheral stem cell collection might start on day 4th of G-CSF treatment for avoiding G-CSF related side effects and complications. (C) 2017 Elsevier Ltd. All rights reserved

Impact of an Established National Donor Registry on Transplant Outcome: Turkok Experience in Turkey

Transplantation and Cellular Therapy (TCT) Meetings of ASTCT and CIBMTR -- FEB 19-23, 2020 -- Orlando, FLWOS: 000516887900445[No abstract available]Amer Soc Transplantat & Cellular Therapy, CIBMT