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Background: The prognosis of myelodysplastic syndromes (MDS) after allogeneic stem cell transplantation is critically determined by cytogenetic abnormalities, as previously defined by International Prognostic Scoring System (IPSS) cytogenetics. It has been shown that a new cytogenetic classification, included in the IPSS-R (cytogenetic-IPSS-R [C-IPSS-R]), can better predict the outcome of untreated MDS patients., Methods: In this study, we assessed the impact of the IPSS-R cytogenetic score (C-IPSS-R) on the outcome of 367 MDS patients transplanted from HLA-identical siblings or HLA allele-matched unrelated donors., Results: According to the C-IPSS-R, 178 patients (48%) fell in the good risk, 102 (28%) in the intermediate risk, 77 (21%) in the poor risk, and 10 (3%) in the very poor risk group. In multivariate analysis, after a median follow-up of 4 years, the poor and very poor-risk categories correlated with shorter overall survival (OS) (4-year OS, 32%; hazard ratio [HR], 1.59; P = 0.009 and OS, 10%; HR, 3.18; P = 0.002, respectively) and higher cumulative incidence of relapse (CIR) (CIR, 52%; HR, 1.82; P = 0.004 and CIR, 60%; HR, 2.44; P = 0.060, respectively)., Conclusions: Overall, the C-IPSS-R changed the IPSS cytogenetic risk only in 8% of cases but identified a new risk group, the very poor C-IPSS-R category, with dismal outcome after allogeneic stem cell transplantation (10% 4-year OS, 60% 4-year CIR). Posttransplantation maintenance therapy should be investigated in prospective trials for patients with high-risk C-IPSS-R karyotypes.

Allogeneic hematopoietic stem cell transplantation (HSCT) is considered the only a curative treatment in patients with higher risk myelodysplastic syndrome (MDS), although demethylating agents (DMA) have been reported to improve survival. The advantage of HSCT over other treatment comes from retrospective studies and the aim of the current study was to prospectively test this hypothesis, analyzing in particular patients from the pre-transplant period to avoid the selection bias of performing transplantation. This study was conducted to compare overall survival in MDS patients candidates to transplantation according to donor availability. The majority of patients (76%) received a treatment with DMA after registration, 69% had a human leukocyte antigen (HLA)-identical donor, 70% of whom were transplanted. Baseline patient and disease characteristics were similar according to donor availability. Four-year overall survival was significantly better in patients with an HLA matched donor (37%) compared to patients without donor (15%). There was also evidence that this overall survival advantage was because of transplantation. Mortality risk was decreased after transplantation but it became significant only after the second year post transplant, because of early transplant-related mortality. Our results appear to justify, in higher risk MDS, a transplantation approach in all potential candidates who have an HLA identical donor.

We performed a retrospective study to identify pretransplantation risk factors for steroid-refractory (SR) acute graft-versus host disease (aGVHD) after allogeneic stem cell transplantation from matched donors in 630 adult patients who underwent transplantation at our center between 2000 and 2012. The cumulative incidence (CI) of SR aGVHD was 11.3% ± 2.3%. The identified independent risk factors were matched unrelated donor (hazard ratio [HR], 2.52; P = .001), female donor for male recipient (HR, 1.84; P = .023) and absence of antithymocyte globulin (HR, 2.02; P = .005). Three risk groups were defined according to the presence of these risk factors. In the whole cohort, the CI of SR aGVHD was 3.5% ± 1.7% in the low-risk group (0 risk factor, n = 115), 9.3% ± 1.6% in the intermediate-risk group (1 risk factor, n = 323), and 19.3% ± 2.9% in the high-risk group (2 or 3 risk factors, n = 192). Our study suggests that pretransplantation characteristics might help identify patients at high risk for SR aGVHD. A risk adapted first-line treatment of aGVHD could be evaluated in those patients., (Copyright © 2015 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Because antithymocyte globulin (ATG) is increasingly used to prevent graft-versus-host disease (GVHD), we performed a retrospective study in adult patients transplanted at our center between January 2008 and December 2012 to explore incidence, characteristics, potential risk factors, and consequences of severe acute hepatotoxicity (SAH) of rabbit ATG (Thymoglobulin) defined as a grade 3 to 4 increase of transaminases. Two hundred twelve patients were included. SAH was diagnosed in 55 patients, representing an incidence of 26%. SAH occurred at a median time of 2 days (range, 1 to 3) after ATG administration, reaching maximum median levels of aspartate aminotransferase and alanine aminotransferase of 8.7 × upper limit of normal (ULN; range, 1.2 to 160) and 11.7 × ULN (range, 4-100), respectively. The International Normalized Ratio was beyond the normal range in 44% of patients. Transaminases decreased below 2 × ULN after a median time of 9 days. We do not report any deleterious impact of SAH on survival, nonrelapse mortality, relapse, or GVHD. Blood systolic pressure < 90 mm Hg during administration of ATG and 2 previous autologous SCT were identified as risk factors for SAH. We believe physicians should be aware of this common toxicity immediately after the administration of ATG to avoid any potential hepatotoxic drug before the resolution and to prevent any risk of hemorrhagic accident., (Copyright © 2015 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

To investigate the role of reduced-intensity allogeneic (RIC-allo) stem cell transplant (SCT) as postremission therapy in adult intermediate-risk patients with acute myelogenous leukemia (AML) with FLT3-ITD or wild-type NPM1 and CEBPA without FLT3-ITD, we conducted a single-center retrospective study between January 2001 and December 2010. Sixty-six patients were included: 37 treated with RIC-alloSCT and 29 with nonallogeneic SCT therapies. Both groups were comparable concerning age, WBC count at diagnosis, gender, karyotype, genotype, and number of courses of chemotherapy to reach complete remission (CR1). Median follow-up after CR1 was 37 months (range, 11-112 months) and 48 months (range, 9-83 months) in the allo and no-allo groups, respectively. In the allo versus no-allo groups, the 3-year cumulative incidence of relapse (CIR) rates were 25% ± 8% versus 61% ± 9%; P = .005. The 3-year nonrelapse mortality (NRM), overall survival (OS), and relapse-free survival (RFS) were 22% ± 7% versus 4% ± 4% (P = .005), 52% ± 9% versus 44% ± 10% (P = .75), and 53% ± 9% versus 35% ± 9% (P = .28), respectively. Multivariate analysis indicated that CIR was reduced by allo (hazard ratio [HR], 0.32; P = .01). A landmark analysis performed at day 185 after CR1 confirmed a lower CIR after allo. RIC-allo reduces the risk of relapse, suggesting a potent graft-versus-leukemia (GVL) effect in these patients at a high risk of relapse., (Copyright © 2012 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: In the era of eculizumab, identifying patients with paroxysmal nocturnal hemoglobinuria who may benefit from allogeneic stem cell transplantation is challenging., Design and Methods: We describe the characteristics and overall survival of 211 patients transplanted for paroxysmal nocturnal hemoglobinuria in 83 EBMT centers from 1978 to 2007. Next, we conducted a comparison with a cohort of 402 non-transplanted patients with paroxysmal nocturnal hemoglobinuria diagnosed between 1950 and 2005 in 92 French centers. We compared the occurrence of complications (i.e. thromboembolism and aplastic anemia) using either an individual or a stratum-matching procedure., Results: After a median follow-up of 5 years, the 5-year overall survival rate ± standard error (%) was 68 ± 3 in the transplanted group (54 ± 7 in the case of thromboembolism, 69 ± 5 in the case of aplastic anemia without thromboembolism and 86 ± 6 in the case of recurrent hemolytic anemia without thromboembolism or aplastic anemia). Only thromboembolism as the indication for transplantation was associated with worse outcome (P=0.03). We identified 24 pairs of transplanted and non-transplanted patients with thromboembolism for the matched comparison, with worse overall survival for the transplanted patients (hazard ratio=10.0; 95% confidence interval, 1.3-78.1; P=0.007). This was confirmed by the global matching procedure (P=0.03). As regards aplastic anemia without thromboembolism, 30 pairs were identified for the matched comparison. It was not observed that transplanted patients had a significantly worse overall survival (hazard ratio=4.0; 95% confidence interval, 0.9-18.9; P=0.06). A global matching procedure was not feasible., Conclusions: Allogeneic stem cell transplantation is probably not a suitable treatment option for life-threatening thromboembolism in paroxysmal nocturnal hemoglobinuria.

A correction to the article "Reduced-toxicity conditioning with fludarabine, once-daily intravenous busulfan, and antithymocyte globulins prior to allogeneic stem cell transplantation: Results of a multicenter prospective phase 2 trial" that was published online in the November 11, 2014 issue is presented.

The impact of in vivo T-cell depletion on transplantation outcomes in patients transplanted with reduced-intensity conditioning (RIC) remains controversial. This study assessed the outcome of 1250 adult patients with de novo AML in first CR (CR1) given PBSC from HLA-identical siblings after chemotherapy-based RIC. A total of 554 patients did not receive any form of in vivo T-cell depletion (control group), whereas antithymocyte globulin (ATG) and alemtuzumab were given in 444 and 252 patients, respectively. The incidences of grade II-IV acute GVHD were 21.4, 17.6 and 10.2% in control, ATG and alemtuzumab patients, respectively (P<0.001). In multivariate analysis, the use of ATG and the use of alemtuzumab were each associated with a lower risk of chronic GVHD (P<0.001 each), but a similar risk of relapse, and of nonrelapse mortality, and similar leukemia-free survival and OS. Further, among patients given BU-based RIC, the use of <6 mg/kg ATG did not increase the risk of relapse (hazard ratio, HR=1.1), whereas there was a suggestion for higher relapse risk in patients given 6 mg/kg ATG (HR=1.4, P=0.08). In summary, these data suggest that a certain amount of in vivo T-cell depletion can be safely used in the conditioning of AML patients in CR1 given PBSC after chemotherapy-based RIC. [ABSTRACT FROM AUTHOR]

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Sclerotic chronic GvHD (cGvHD) is one of the most severe complications after allo-hematopoietic stem cell transplantation (HSCT). Risk factors associated with this complication remain not very well defined. With the aim to define a pre-transplantation risk profile, we have conducted a French retrospective analysis in 705 consecutive patients between 2005 and 2010. Analyses to determine pre-transplantation risk factors included as variables: patient and donor age, kind of donor, HLA matching, ABO matching, sex-matching, diagnosis, stem cell source, gender, GvHD prophylaxis and antithymocyte globulin (ATG) in the conditioning regimen. The cumulative incidence of sclerotic cGvHD was 18% (95% CI, 16.6-19.6) 3 years after onset of cGvHD. In univariate analysis, we found a significantly lower number of sclerotic cGvHD form in patients transplanted from cord blood cells (P=0.0021), in patients with a one mismatched donor (P=0.041) and in patients who had received ATG in the conditioning regimen (P=0.002). In multivariate analysis, factors associated with an increased risk of sclerotic cGvHD were young patient age, multiple myeloma and PBSC as the stem cell source. ATG in conditioning regimen and cord blood unit as the stem cell source were associated with a lower risk. [ABSTRACT FROM AUTHOR]

Progression of Philadelphia-negative myeloproliferative (MPN) or myelodysplastic/myeloproliferative neoplasms (MDS/MPN) to acute myeloid leukemia (AML) is an adverse event in the course of the disease. Although allogeneic hematopoietic SCT (allo-SCT) is considered as the only curative therapy, few data exist on the outcome of patients with Philadelphia-negative MPN or MDS/MPN in blast phase who received an allo-SCT. Sixty patients were included in this retrospective study. AML was secondary to an MPN in 43 cases, whereas AML evolved from an MDS/MPN in 17 cases. Patients received allo-SCT in CR or advanced disease in 26 cases and 34 cases, respectively. With a median follow-up of 31 months (range, 25-44), OS and leukemia-free survival (LFS) were, respectively, 18% and 9% at 3 years. CR at transplant was associated with an improved LFS in univariate and multivariate analysis. The 3-year LFS was 18% for patients undergoing allo-SCT in CR versus 3% in advanced disease (P=0.008). Absence of thrombosis and an intermediate or favorable AML karyotype were associated with an improved outcome for patients who received allo-SCT in CR. New strategies are needed to improve the outcome of patients with MPN-MDS/MPN in blast phase. [ABSTRACT FROM AUTHOR]

This report investigated the impact of graft-versus-host disease (GVHD) on transplantation outcomes in 1859 acute myeloid leukemia patients given allogeneic peripheral blood stem cells after reduced-intensity conditioning (RIC allo-SCT). Grade I acute GVHD was associated with a lower risk of relapse (hazards ratio (HR)=0.7, P=0.02) translating into a trend for better overall survival (OS; HR=1.3; P=0.07). Grade II acute GVHD had no net impact on OS, while grade III-IV acute GVHD was associated with a worse OS (HR=0.4, P<0.0.001) owing to high risk of nonrelapse mortality (NRM; HR=5.2, P<0.0001). In time-dependent multivariate Cox analyses, limited chronic GVHD tended to be associated with a lower risk of relapse (HR=0.72; P=0.07) translating into a better OS (HR=1.8; P<0.001), while extensive chronic GVHD was associated with a lower risk of relapse (HR=0.65; P=0.02) but also with higher NRM (HR=3.5; P<0.001) and thus had no net impact on OS. In-vivo T-cell depletion with antithymocyte globulin (ATG) or alemtuzumab was successful at preventing extensive chronic GVHD (P<0.001), but without improving OS for ATG and even with worsening OS for alemtuzumab (HR=0.65; P=0.001). These results highlight the role of the immune-mediated graft-versus-leukemia effect in the RIC allo-SCT setting, but also the need for improving the prevention and treatment of severe GVHD. [ABSTRACT FROM AUTHOR]

This was a retrospective multicenter study including 44 acute leukaemia patients who have received allogeneic haematopoietic SCT (allo-HSCT) after prior exposure to Gemtuzumab Ozogamicin (GO) + chemotherapy. Median interval between last administration of GO and allo-HSCT was 4.2 (range, 0.8–26.3) months. At time of allo-HSCT, 33 patients were in CR. The majority of patients (n=36) received a reduced-intensity conditioning (RIC) regimen before allo-HSCT. All but one patient received low-dose heparin for veno-occlusive disease (VOD) prophylaxis. With a median follow-up of 15 (range, 1.1–63) months, overall survival and disease-free survival after allo-HSCT were 45% (95% confidence interval (CI), 30–61%) and 38% (95% CI, 24–54%) at 2 years, respectively. The cumulative incidence of grade 3–4 hyperbilirubinemia was 13.5% (n=6), with this being 21% in patients with a short (3.5 months) GO-allo-HSCT interval (n=4/19) vs 8% in all others (P=NS). Overall, the cumulative incidence of VOD was 7% (n=3), with this being 10.5% (n=2/19) in patients with a short GO-allograft interval (3.5 months) vs 4% (n=1/25) for all others (P=NS), and 5.5% (n=2/36) in patients receiving an RIC regimen vs 12.5% for the others (n=1/8) (P=NS). These results suggest that GO-based chemotherapy before allo-HSCT is feasible and does not result in an excessive rate of liver toxicity, especially VOD, after allo-HSCT. [ABSTRACT FROM AUTHOR]

Rationale: Allogeneic hematopoietic stem-cell transplantation (Allo-HSCT) recipients are still believed to be poor candidates for ICU management. Methods: We investigated outcomes and determinants of mortality in a large multicenter retrospective cohort of Allo-HSCT patients admitted between January 1, 2015, and December 31, 2020, to 14 French ICUs. The primary endpoint was 90-day mortality. Measurements and Main Results: In total, 1,164 patients were admitted throughout the study period. At the time of ICU admission, 765 (66%) patients presented with multiple organ dysfunction, including acute respiratory failure in 40% (n = 461). The median sepsis-related organ failure assessment score was 6 (interquartile range, 4–8). Invasive mechanical ventilation, renal replacement therapy, and vasopressors were required in 438 (38%), 221 (19%), and 468 (41%) patients, respectively. ICU mortality was 26% (302 deaths). Ninety-day, 1-year, and 3-year mortality rates were 48%, 63%, and 70%, respectively. By multivariable analysis, age > 56 years (odds ratio [OR], 2.0 [95% confidence interval (CI), 1.53–2.60]; P < 0.001), time from Allo-HSCT to ICU admission between 30 and 90 days (OR, 1.68 [95% CI, 1.17–2.40]; P = 0.005), corticosteroid-refractory acute graft-versus-host disease (OR, 1.63 [95% CI, 1.38–1.93]; P < 0.001), need for vasopressors (OR, 1.9 [95% CI, 1.42–2.55]; P < 0.001), and mechanical ventilation (OR, 3.1 [95% CI, 2.29–4.18]; P < 0.001) were independently associated with 90-day mortality. In patients requiring mechanical ventilation, mortality rates ranged from 39% (no other risk factors for mortality) to 100% (four associated risk factors for mortality). Conclusions: Most critically ill Allo-HSCT recipients survive their ICU stays, including those requiring mechanical ventilation, with an overall 90-day survival rate reaching 51.8%. A careful assessment of goals of care is required in patients with two or more risk factors for mortality. [ABSTRACT FROM AUTHOR]

Adult T-cell Leukemia/Lymphoma (ATLL) is a rare but aggressive malignancy associated with the human T-cell lymphotropic virus type 1 (HTLV-1). ATLL is a challenging malignancy characterized by its aggressive nature and poor prognosis. Despite advancements in treatment, relapse rates remain high. Donor lymphocyte infusion (DLI) is a promising therapeutic option post-hematopoietic stem cell transplantation (HSCT) to prevent relapse. However, the prophylactic use of DLI in ATLL patients remains underexplored. We report the case of a 45-year-old female diagnosed with ATLL. Following induction chemotherapy and successful HSCT, a modified prophylactic DLI regimen was administered, consisting of gradually increasing doses of donor lymphocytes. The patient demonstrated a favorable response with no significant graft-versus-host disease (GVHD) and maintained remission over a 40-month follow-up period, suggesting a potential benefit of this approach. This case highlights the potential efficacy and safety of modified prophylactic DLI in ATLL patients, warranting further investigation. Our findings suggest that modified prophylactic DLI is a viable option for ATLL patients post-HSCT, offering a balance between efficacy and safety. Future research should focus on optimizing DLI protocols and exploring biomarkers for response prediction. [ABSTRACT FROM AUTHOR]

The introduction of novel agents dramatically improved response and outcomes of multiple myeloma (MM) and led to a sharp decline in the use of allogeneic hematopoietic stem-cell transplantation (allo-HSCT). Thus, recent guidelines do not recommend anymore allo-HSCT as consolidation in the first-line treatment of newly diagnosed MM, even in high-risk patients. In a relapsed/refractory setting, allo-HSCT is not routinely recommended but should only be performed within clinical trials in young and high-risk patients. Nonetheless, allo-HSCT still represents a potential curative approach that has been used for decades in the treatment of MM and plasma cell neoplasms with favorable results and may still represent a treatment option for carefully selected patients. Despite that promising results were obtained with CAR T-cell therapies and bispecific antibodies in triple- and penta-exposed/refractory MM, these patients will inevitably relapse. To date, less is known about outcomes of allo-HSCT in patients exposed to novel immunotherapeutic drugs. Therefore, allo-HSCT could represent a reasonable treatment choice for younger and high-risk patients who have relapsed after CAR T-cell therapies and bispecific antibodies as well as an alternative for patients not eligible to these treatments and in those countries where immunotherapies are not yet available. In the choice of conditioning, reduced intensity conditioning regimens are currently recommended for the lower toxicity and mortality. Moreover, the use of alternative donors, particularly haploidentical, has progressively increased in last years with results comparable to full matched donors. Finally, post-transplantation maintenance strategies are encouraged whenever feasible. [ABSTRACT FROM AUTHOR]

Introduction: Carmustine (BCNU), etoposide, cytarabine, and melphalan (BEAM) are a widely used high-dose chemotherapy regimen for autologous stem cell transplantation transplant (ASCT) in lymphoid malignancies. During BCNU shortages, some centers switched to fotemustine-substituted BEAM (FEAM). Neutropenic enterocolitis (NEC) is a life-threatening complication occurring after intestinal mucosa damage related to intensive chemotherapy. NEC mortality may be up to 30%-50%. In our study, we compared NEC incidence, symptoms, mortality, and transplant outcome in terms of overall survival (OS) and progression-free survival (PFS) in the BEAM vs. FEAM groups. Furthermore, we compared the cost of hospitalization of patients who did vs. patients who did not experience a NEC episode (NECe). Methods: A total of 191 patients were enrolled in this study (N = 129 and N = 62 were conditioned with BEAM and FEAM, respectively). All patients received bedside high-resolution ultrasound (US) for NEC diagnosis. Results and discussion: NEC incidence and NEC-related mortality were similar in the BEAM and FEAM groups (31% and 40.3%, p = 0.653, and 5% and 8%, p = 0.627, respectively). At a median follow-up of 116 months, no difference was noted between BEAM vs. FEAM groups in terms of OS and PFS (p = 0.181 and p = 0.978, respectively). BEAM appeared equivalent to FEAM in terms of NEC incidence and efficacy. The high incidence of NEC and the low mortality is related to a timely US diagnosis and prompt treatment. US knowledge in NEC diagnosis allows to have comparable days of hospitalization of patients NECpos vs. patients NECneg. The cost analysis of NECpos vs. NECneg has been also performed. [ABSTRACT FROM AUTHOR]

Refractory acute myeloid leukaemia is very difficult to treat and represents an unmet clinical need. In recent years, new drugs and combinations of drugs have been tested in this category, with encouraging results. However, all treated patients relapsed and died from the disease. The only curative option is allogeneic transplantation through a graft from a healthy donor immune system. Using myeloablative conditioning regimens, the median overall survival regimens is 19%. Several so-called sequential induction chemotherapies followed by allogeneic transplantation conditioned by reduced intensity regimens have been developed, improving the overall survival to 25–57%. In the allogeneic transplantation field, continuous improvements in practices, particularly regarding graft versus host disease prevention, infection prevention, and treatment, have allowed us to observe improvements in survival rates. This is true mainly for patients in complete remission before transplantation and less so for refractory patients. However, full myeloablative regimens are toxic and carry a high risk of treatment-related mortality. In this review, we describe the results obtained with the different modalities used in more recent retrospective and prospective studies. Based on these findings, we speculate how allogeneic stem cell transplantation could be modified to maximise its therapeutic effect on refractory acute myeloid leukaemia. [ABSTRACT FROM AUTHOR]

The article presents a retrospective study which examines the use of early allogeneic stem cell transplantation (SCT) in first response for patients with peripheral T-cell lymphomas (PTCL). Findings reveal that patients with high-risk PTCL might benefit from early transplantation. Moreover, it suggests the effect of graft versus host disease (GVHD) in patients with high-risk PTCL.

Therapeutic donor lymphocyte infusions (tDLI) are used to reinforce the graft-versus-leukemia (GvL) effect in relapse after allogeneic stem cell transplantation (alloSCT). In contrast, the role of prophylactic DLI (proDLI) in preventing leukemia relapse has been less clearly established, although supported by retrospective, case-control, and registry analyses. We report a prospective, monocentric, ten year cohort of patients with high risk acute leukemias (AL) or myelodysplasia (MDS) in whom proDLI were applied beyond day +120 post alloSCT to compensate for lack of GvL. 272 consecutive allotransplanted AL or MDS patients in complete remission and off immunosuppression at day +120 were stratified according to the prior appearance of relevant GvHD (acute GvHD °II-IV or extensive chronic GvHD) as a clinical indicator for GvL. Escalating doses of unmodified proDLI were applied to 72/272 patients without prior relevant GvHD. Conversely, 157/272 patients with prior spontaneous GvHD did not receive proDLI, nor did 43/272 patients with contraindications (uncontrolled infections, patient refusal, DLI unavailability). By day 160-landmark analysis (median day of first DLI application), proDLI recipients had significantly higher five-year overall (OS) and disease free survival (DFS) (77% and 67%) than patients with spontaneous GvHD (54% and 53%) or with contraindications (46% and 45%) (p=0.003). Relapse incidence for patients with proDLI (30%) or spontaneous GvHD (29%) was significantly lower than in patients with contraindications (39%; p=0.021). With similar GvHD incidence beyond day +160, non-relapse mortality (NRM) was less with proDLI (5%) than without proDLI (18%; p=0.036). In conclusion, proDLI may be able to compensate for lack of GvL in alloSCT recipients with high risk AL or MDS. [ABSTRACT FROM AUTHOR]

Objective: Steroids-refractory (SR) acute graft-versus-host disease (aGVHD) is a life-threatening condition in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT), but the optimal second-line therapy still has not been established. We aimed to perform a systematic review and meta-analysis of randomized controlled trials (RCTs) to compare the efficacy and safety of different second-line therapy regimens. Methods: Literature search in MEDLINE, Embase, Cochrane Library and China Biology Medicine databases were performed to retrieve RCTs comparing the efficacy and safety of different therapy regimens for patients with SR aGVHD. Meta-analysis was conducted with Review Manager version 5.3. The primary outcome is the overall response rate (ORR) at day 28. Pooled relative risk (RR) and 95% confidence interval (CI) were calculated with the Mantel-Haenszel method. Results: Eight eligible RCTs were included, involving 1127 patients with SR aGVHD and a broad range of second-line therapy regimens. Meta-analysis of 3 trials investigating the effects of adding mesenchymal stroma cells (MSCs) to other second-line therapy regimens suggested that the addition of MSCs is associated with significantly improvement in ORR at day 28 (RR = 1.15, 95% CI = 1.01-1.32, P = 0.04), especially in patients with severe (grade III-IV or grade C-D) aGVHD (RR = 1.26, 95% CI = 1.04-1.52, P = 0.02) and patients with multiorgan involved (RR = 1.27, 95% CI = 1.05-1.55, P = 0.01). No significant difference was observed betwwen the MSCs group and control group in consideration of overall survival and serious adverse events. Treatment outcomes of the other trials were comprehensively reviewed, ruxolitinib showed significantly higher ORR and complete response rate at day 28, higher durable overall response at day 56 and longer failure-free survival in comparison with other regimens; inolimomab shows similar 1-year therapy success rate but superior long-term overall survial in comparison with anti-thymocyte globulin, other comparisons did not show significant differences in efficacy. Conclusions: Adding MSCs to other second-line therapy regimens is associated with significantly improved ORR, ruxolitinib showed significantly better efficacy outcomes in comparison with other regimens in patients with SR aGVHD. Further well-designed RCTs and integrated studies are required to determine the optimal treatment. [ABSTRACT FROM AUTHOR]

Allogeneic cell therapies, defined by genetically mismatched transplantation, have the potential to become a cost-effective solution for cell-based cancer immunotherapy. However, this type of therapy is often accompanied by the development of graft-versus-host disease (GvHD), induced by the mismatched major histocompatibility complex (MHC) between healthy donors and recipients, leading to severe complications and death. To address this issue and increase the potential for allogeneic cell therapies in clinical practice, minimizing GvHD is a crucial challenge. Innate T cells, encompassing subsets of T lymphocytes including mucosal-associated invariant T (MAIT) cells, invariant natural killer T (iNKT) cells, and gamma delta T (γδ T) cells, offer a promising solution. These cells express MHC-independent T-cell receptors (TCRs), allowing them to avoid MHC recognition and thus GvHD. This review examines the biology of these three innate T-cell populations, evaluates research on their roles in GvHD modulation and allogeneic stem cell transplantation (allo HSCT), and explores the potential futures for these therapies. [ABSTRACT FROM AUTHOR]

Allogeneic hematopoietic stem cell transplantation (HSCT) is an effective treatment for acute myeloid leukemia (AML). Pediatric patients with AML who relapse after HSCT have an extremely poor prognosis. We performed a retrospective study of pediatric patients diagnosed with AML from August 2015 to October 2019 who were treated with HSCT. Kaplan-Meier analyses were used to evaluate overall survival (OS), event-free survival (EFS), and cumulative recurrence rate (CRR). Cox regression analysis was used to determine the association between the baseline characteristics and relapse. A total of 37 pediatric patients met the inclusion criteria. Twenty-eight (75.7%) patients survived, and 9 (24.3%) patients died. The OS rates of AML patients treated with HSCT were 89.2% ± 5.1%, 75.7% ± 7.1%, and 75.7% ± 7.1% at 1, 3, and 5 years, respectively, and the CRRs were 11.4% ± 5.4%, 24.7% ± 7.7%, and 33.1% ± 10.4% at 1, 3, and 5 years after HSCT, respectively; four of nine children who relapsed after transplantation died. Induction with etoposide rather than homoharringtonine and fungal infections could be high-risk factors for recurrence after transplantation. The association between homoharringtoninebased induction therapy and a low recurrence rate persisted after adjusting for age, sex, risk stratification, fusion genes, and fungal infections. This study clarifies the clinical features and poor prognosis of post-transplant relapse in pediatric AML and indicates the urgent need for effective therapy for patients who relapse after HSCT. [ABSTRACT FROM AUTHOR]

The contribution of lymphocyte subset composition of the graft on the outcomes following haploidentical peripheral blood stem cell transplantation (haploPBSCT) is not fully elucidated. We retrospectively analyzed 314 patients with hematological malignancies who underwent haploPBSCT from 2016 to 2020 in our center. We obtained a cutoff value of CD3+ T cell dose (2.96 × 108/kg) that separated the risk of II-IV acute graft-versus-host disease (aGvHD) and divided patients into the low CD3+ T cell dose group (CD3+ low) and the high CD3+ T cell dose (CD3+ high) group. Significantly higher incidences of I-IV aGvHD, II-IV aGvHD, and III-IV aGvHD were identified in the CD3+ high group (50.8%, 19.8%, and 8.1% in the high group, 23.1%, 6.0%, and 0.9% in the low group, P < 0.0001, P = 0.002, and P = 0.02, respectively). We found that CD4+ T cell and its naïve and memory subpopulations of grafts had a significant impact on aGvHD (P = 0.005, P = 0.018, and P = 0.044). Besides, we found an inferior reconstitution of natural killer (NK) cells in the CD3+ high group than in the low group within the first-year posttransplant (239 cells/µL vs 338 cells/µL, P = 0.0003). No differences in engraftment, chronic GvHD (cGvHD), relapse rate, transplant-related mortality (TRM), and overall survival (OS) were identified between the two groups. In conclusion, our study found that a high CD3+ T cell dose led to a high risk of aGvHD and inferior reconstitution of NK cells in the haploPBSCT setting. In the future, carefully manipulating the composition of lymphocyte subsets of grafts might reduce the risk of aGvHD and improve the transplant outcome. [ABSTRACT FROM AUTHOR]

Introduction: The overall outcome of patients with refractory AML (rAML) remains poor. Though allogeneic hematopoietic stem cell transplantation (allo-HSCT) is considered as the only curative therapy, it is routinely recommended only for patients after remission with salvage chemotherapy. Objective: In this study, we evaluated the impact of salvage chemotherapy or allo-HSCT on the overall outcome in rAML. Methods: We collected the clinical data of 220 patients from 4 medical centers and performed retrospective analysis of prognosis factors, including salvage chemotherapy, intensity of chemotherapy, and allo-HSCT. Results: A total of 29 patients received allo-HSCT directly without salvage chemotherapy, 26 patients achieved complete remission (CR) or complete remission with incomplete hematological recovery (CRi) after transplantation and 4-year leukemia-free survival (LFS) and overall survival (OS) were 45.0 ± 10.7 and 51.0 ± 10.6%, respectively. Another 191 patients received salvage chemotherapy and 81 (42.2%) achieved CR or CRi. Thirty-four patients among them underwent subsequent allo-HSCT with 4-year LFS and OS of 46.0 ± 8.8 and 46.2 ± 9.0%. The 4-year LFS and OS in 26 patients who failed to obtain CR or CRi but received allo-HSCT with active disease were 32.9 ± 10.0 and 36.9 ± 10.8%, respectively. For patients who received salvage chemotherapy but not allo-HSCT, few of them became long-term survivors. In multivariate analysis, salvage chemotherapy and the intensity of chemotherapy failed to have significant impact on both OS and LFS. Allo-HSCT was the only prognostic factor for improved OS and LFS in multivariate analysis. Conclusions: These results indicate the benefit of allo-HSCT in patients with rAML and direct allo-HSCT without salvage chemotherapy could be treatment option. [ABSTRACT FROM AUTHOR]

Background: Acute myeloid leukemia (AML) with antecedent hematological disease (s-AML) and treatment-related AML (t-AML) predicts poor prognosis. Intensive treatment protocols of those high-risk patients should consider allogeneic stem cell transplantation (allo-HSCT) in first complete remission (CR). Despite allo-HSCT, relapse rate remains high. Induction chemotherapy with liposomal cytarabine and daunorubicin (CPX-351) has been approved for patients with AML with myeloid-related changes (AML-MRC) or t-AML based on improved survival and remission rates compared to standard 7 + 3 induction. Patients and methods: 110 patients with newly diagnosed s-AML or t-AML at a university hospital were analyzed retrospectively. Median age was 62 years (24–77 years). A total of 65 patients with s-AML after MDS (59%) and 23 patients (20.9%) with t-AML were included. Induction chemotherapy consisted of intermediate-dosed cytarabine (ID-AraC) in combination with idarubicin (patients up to 60 years) or mitoxantrone (patients over 60 years). In patients subsequently undergoing allo-HSCT, reduced conditioning regimens (RIC) were applied prior to transplantation in 47 of 62 patients (76%). Results: Induction chemotherapy with ID-AraC resulted in an overall response rate of 83% including complete remission (CR/CRi) in 69 patients (63%) with a low rate of early death (2.7%). Most relevant non-hematologic toxicity consisted of infectious complications including sepsis with need of intensive care treatment in five patients (4.5%) and proven or probable invasive fungal disease in eight patients (7.2%). Relapse-free survival (RFS), event-free survival (EFS) and overall survival (OS) of the whole cohort were 19 months (0–167), 10 months (0–234) and 15 months (0–234), respectively (p < 0.0001). A significant improvement of OS was observed in patients who underwent allo-HSCT compared to those without subsequent allo-HSCT: 9 vs. 46 months, p < 0.0001. Rate of transplantation-related mortality (TRM) in the early phase post allo-HSCT was low (0.9% at day 30 and 1.8% at day 90, respectively). RIC conditioning results in OS rate of 60% after 60 months post allo-HSCT (median OS not reached). Conclusion: S-AML and t-AML patients receiving induction chemotherapy with intermediate-dosed cytarabine showed satisfactory response rate and consolidation therapy with allo-HSCT after full or reduced-intensity conditioning further improved survival in these patients with similar outcome as reported for CPX-351. [ABSTRACT FROM AUTHOR]

Autoimmune disease (AD) may occur after allogeneic hematopoietic stem cell transplantation (HSCT). The autoimmune mechanism seems to be related to an imbalance of the immune regulation effect of T-regulatory lymphocytes on autoreactive T-lymphocytes. ADs include hematological ADs (HADs) and nonhematologic ADs (NHADs) involving organs such as thyroid, peripheral and central nervous system, skin, liver, connective tissue, gastrointestinal tract, and kidney. To identify the risk factors for ADs, to report their clinical characteristics, and to discuss new approaches represent the areas covered in this review. Some risk factors for HAD and NHAD are common and include nonmalignant diseases, young age, cord blood as a stem cell source, conditioning regimens without total body irradiation, alemtuzumab, antithymocyte globulin, T-cell-depleted transplant, some viral infection, mixed chimerism, and chronic Graft versus Host Disease. In NHADs, the detection of autoantibodies is more frequent and the transfer of autoimmunity from the donor to the recipient represents the pathogenetic mechanism responsible for these complications. New therapeutic approaches such as bortezomib, daratumumab, sirolimus, eculizumab, and eltrombopag appear to be promising in terms of better efficacy and reduced toxicity compared to traditional therapies. New horizons based on personalized therapies will allow us to improve the prognosis of AD. [ABSTRACT FROM AUTHOR]

Thrombopoietin receptor agonists (TPO-RA) are currently indicated for the treatment of chronic immune thrombocytopenia and relapsed refractory aplastic anemia. However, the off-label use of these drugs is more and more frequent, including in the setting of aplasia secondary to chemotherapy and hemopoietic stem cell transplant (SCT). Growing evidence suggests that mechanisms of action of TPO-RA go beyond the TPO-receptor stimulation and point at the immunomodulating properties of these drugs. Here, we present a case of prolonged bone marrow aplasia secondary to autologous SCT treated with eltrombopag. We describe the clinical efficacy and the immunomodulating effect of this drug on inflammatory cytokine profile and bone marrow histology. Furthermore, we provide a review of the most recent literature highlighting the efficacy and safety of TPO-RA after SCT and chemotherapy for hematologic conditions. [ABSTRACT FROM AUTHOR]

Graft-versus-host disease (GvHD) of the skin is a severe allo-immune reaction and complication following allogeneic stem cell transplantation. Over the past years, intensive pre-clinical research has led to an improved understanding of the pathophysiology of acute and to a lesser extend chronic GvHD. This has translated into the approval of several new agents for the treatment of both forms of GvHD. This review summarizes the most recent advances in underlying pathomechanisms, clinical trials and newly approved agents for GvHD, with a special focus on skin involvement. [ABSTRACT FROM AUTHOR]

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is one of the consolidation modalities for adult patients with T-cell lymphoblastic lymphoma (T-LBL). However, the optimal conditioning regimen needs to be explored. In the present study, 40 patients with T-LBL undergoing allo-HSCT were retrospectively analyzed, including 23/40 (57.5%) with total body irradiation (TBI)–based conditioning regimen and 17/40 (42.5%) with busulfan (BU)-based regimen. TBI–based regimen significantly increased the cumulative incidence (CI) of grade II to IV acute graft-versus-host disease (aGvHD) as compared with BU-based regimen (13.0% vs 0%, P = 0.000). The relapse risk was significantly lowered in TBI-based group with a 2-year CI of relapse (CIR) of 9.1% as compared with that of 49.6% in BU-based group (P = 0.008). The 1-year and 2-year non-relapse mortalities (NRMs) for all patients were 5.0% and 10.3%, respectively. The 1-year and 2-year NRMs were 8.9% and 16.0% in TBI-based group, and 0.00% and 0.00% in BU-based group (P = 0.140). The 2-year probabilities of overall survival (OS) and relapse-free survival (RFS) were 83.0% [95% confidence interval, 63.4%–100%] and 74.0% (95% confidence interval, 54.4%–93.6%) in TBI-based group, which were higher than that of 35.0% (95% confidence interval, 0.0%–72.2%) and 50.0% (95% confidence interval, 24.5%–75.4%) in BU-based group, respectively (P = 0.020 for OS and P = 0.081 for RFS). In multivariate analysis, TBI-based regimen significantly reduced the risk of relapse [subdistribution hazard ratio (SHR) = 0.030, 95% CI, 0.002–0.040, P = 0.000] and improved the OS [hazard ratio (HR) 0.121, 95% CI, 0.021–0.683, P = 0.017] as an independent prognostic factor. These results suggested that TBI-based regimen might be an optimal choice for adult patients with T-LBL undergoing allo-HSCT. [ABSTRACT FROM AUTHOR]

Haploidentical transplantation has extended the availability of allogeneic hematopoietic stem cell transplant (alloHCT) to almost all patients. Sequential conditioning regimens have been proposed for the treatment of hematological active disease. Whether these new transplantation procedures affect the prognosis of critically ill alloHCT recipients remains unknown. We evaluated this question in a retrospective study including consecutive alloHCT patients admitted to the intensive care unit of a tertiary academic center from 2010 to 2017. During the study period, 412 alloHCTs were performed and 110 (27%) patients—median age 55 (36–64) years—were admitted to ICU in a median time of 58.5 (14–245) days after alloHCT. Twenty-nine (26%) patients had received a haploidentical graft and 34 (31%) a sequential conditioning. Median SOFA score was 9 (6–11). Invasive mechanical ventilation (MV) was required in 61 (55%) patients. Fifty-six (51%) patients died in the hospital. Independent factors associated with in-hospital mortality were as follows: MV (OR=8.44 [95% CI 3.30–23.19], p<0.001), delta SOFA between day 3 and day 1 (OR=1.60 [95% CI 1.31–2.05], p<0.0001), and sequential conditioning (OR=3.7 [95% CI 1.14–12.92], p=0.033). Sequential conditioning was also independently associated with decreased overall survival (HR=1.86 [95% CI 1.05–3.31], p=0.03). Other independent factors associated with reduced overall survival were HCT-specific comorbidity index ≥2 (HR=1.76 [95% CI 1.10–2.84], p=0.02), acute GVHD grade ≥2 (HR=1.88 [95% CI 1.14–3.10], p=0.01), MV (HR=2.37 [95% CI 1.38–4.07, p=0.002), and vasopressors (HR=2.21 [95% CI 1.38–3.54], p=0.001). Haploidentical transplantation did not affect outcome. Larger multicenter studies are warranted to confirm these results. [ABSTRACT FROM AUTHOR]

The role of allogeneic hematopoietic stem cell transplantation (allo-SCT) in multiple myeloma is controversial. We analyzed the results of 205 patients transplanted in one center during 2000-2017. Transplantation was performed on 75 patients without a previous autologous SCT (upfront-allo), on 74 as tandem transplant (auto-allo), and on 56 patients after relapse. Median overall survival (OS) was 9.9 years for upfront-allo, 11.2 years for auto-allo, and 3.9 years for the relapse group (p = 0.015). Progression-free survival (PFS) was 2.4, 2.4, and 0.9 years, respectively (p < 0.001). Non-relapse mortality at 5 years was 8% overall, with no significant difference between the groups. Post-relapse survival was 4.1 years for upfront-allo and auto-allo, and 2.6 years for the relapse group (p = 0.066). Survival of high-risk patients was reduced. In multivariate analysis, the auto-allo group had improved OS and chronic graft-versus-host disease was advantageous in terms of PFS, OS, and relapse incidence. Late relapses occurred in all groups. Allo-SCT resulted in long-term survival in a small subgroup of patients. Our results indicate that auto-allo-SCT is feasible and could be considered for younger patients in the upfront setting. [ABSTRACT FROM AUTHOR]

A head-to-head comparison of outcomes of unrelated donor allogeneic peripheral blood stem cell transplantation for AML between reduced intensity conditioning (RIC) and myeloablative conditioning (MAC) regimens using thymoglobulin for GVHD prophylaxis is limited. We evaluated outcomes of 122 AML patients who received either busulfan (Bu)/fludarabine (Flu)/low-dose total body irradiation (TBI) as RIC (n = 64, 52%) or Bu/Flu as MAC (n = 58, 48%), and thymoglobulin 4.5 mg/kg total dose between day − 3 to − 1 for GVHD prophylaxis. Grades III–IV acute GVHD (aGVHD) was lower with Bu/Flu/TBI compared with Bu/Flu (6.2% vs 26.1%, p = 0.009). At 1 year, Bu/Flu/TBI was associated with similar chronic GVHD (41.2% vs 44.8%, p = 0.75), OS (61.9% vs 56.9%, p = 0.69), relapse rate (29.9% vs 20.7%, p = 0.24), relapse-free survival (52.8% vs 50%, p = 0.80), non-relapse mortality (17.4% vs 29.3%, p = 0.41), and GVHD-free relapse-free survival (24.2% vs 27.5%, p = 0.80) compared with Bu/Flu. Multivariable analysis did not reveal any difference in outcomes between both regimens. In summary, thymoglobulin at 4.5 mg/kg did not have any adverse impact on survival when used with RIC regimen. Both Bu/Flu/TBI and Bu/Flu conditioning regimens yielded similar survival. [ABSTRACT FROM AUTHOR]

The Acute Leukemia Working Party (ALWP) of the EBMT assessed the outcome of allogeneic stem cell transplantation (alloSCT) in patients with relapsed/refractory AML (r/rAML) evaluating six sequential conditioning regimens (SR) groups. A total of 2132 patients were included. LFS at 2 years was 28.9%, 33.6%, 35.3%, 20.6%, 24.4%, and 27% for the FLAMSA-TBI4, FLAMSA-Chemo, Mel-Flu-TBI8, Mel-Treo-Flu, Thio-ETO-Cy-Bu2-Flu, and Clo-ARAC-(Bu2/TBI4)-Cy groups, respectively. In patients <55 years of age Mel-Flu-TBI8 had the best LFS, which was statistically significant only in comparison to the Mel-Treo-Flu group, while in patients ≥55 years LFS was best with FLAMSA-Chemo without significant differences compared to FLAMSA-TBI4 and Mel-Flu-TBI8. Furthermore, best NRM rates were obtained with the two FLAMSA regimens groups. Our study suggests that in younger (<55 years) patients a more intense regimen might be used whereas in older (≥55 years) patients the focus might be more on tolerability. [ABSTRACT FROM AUTHOR]

The incidence, risk factors, and prognostic significance of extramedullary involvement (EMI) in adult patients with acute myeloid leukemia (AML) have not been established yet. This study analyzed clinical and biological characteristics, the impact on prognosis, and the cumulative incidence of EMI in a monocentric retrospective series. All adult patients diagnosed with AML observed in our institution between January 2010 and December 2017 were included in the analysis. Overall, 346 AMLs were analyzed. The incidence of EMI was 11% (38 patients). The involved sites were: skin (66%), central nervous system (CNS) (23%), pleura (7%), lymph nodes (5%), peritoneum (2%), spleen (2%), pancreas (2%), breasts (2%) and bones (2%). Most patients (91%) had only one EMI site, while 9% had multiple sites affected at the same time. Twenty-four (63%) patients showed signs of EMI at presentation, while extramedullary relapse occurred in 10 patients (26%); 4 patients had EMI both at presentation and relapse. EMI had a significantly higher frequency in patients with monocytic and myelo-monocytic leukemia subtypes (p<0,0001), CD117-negative (p=0,03) at flow cytometry analysis, MLL rearrangements (p=0.001), trisomy 8 (p=0,02). An analysis regarding treatment, overall survival (OS), and disease-free survival (DFS) was performed only on the 28 patients who experienced EMI at the onset of their disease; one EMI patient receiving best supportive care was excluded from OS analysis. The other 27 patients were treated with: conventional chemotherapy (21 patients), hypomethylating agents (5 patients), and low dose cytarabine (1 patient); 8 patients only (28.5%) received an allogeneic stem cell transplantation (allo-HSCT). After induction therapy, complete remission (CR) rate was 22%, with a median DFS of 7.4 months. The median OS of all 27 EMI patients was 11.6 months (range 2-79); this resulted significantly longer for the 8 EMI patients who undergone allo-HSCT than those (19 patients) who did not receive this procedure (16.7 vs. 8.2 months respectively, p=0.02). Univariate and multivariate analyses showed that undergoing allo-HSCT and achieving CR were the main positive prognostic factors for our population's survival (p<0,0001). This study confirms the poor prognosis for EMI patients. Allo-HSCT, applicable however only in some cases, seems to have a crucial role in these patients' therapeutic approach, being associated with a better prognosis. [ABSTRACT FROM AUTHOR]

Acute GVHD (aGVHD) is a significant complication after allogeneic hematopoietic cell transplantation (HCT), occurring in up to 70% of HCT recipients. Steroid-refractory aGVHD represents a subset of patients failing initial therapy and is particularly morbid, with only 30% of patients surviving long term. Better therapies are urgently required for these patients. Here, we discuss recent advancements in the management of SR-aGVHD. We review the currently available therapies for SR-aGVHD including the results of the REACH1 and REACH2 trials, which provide the basis for the use of ruxolitinib for the treatment of SR-aGVHD. We additionally discuss newer agents under clinical investigation and will highlight the niche these agents may fill to further improve outcomes in aGVHD patient care. [ABSTRACT FROM AUTHOR]

Allogeneic hematopoietic cell transplantation (alloHCT) has been used as cellular immunotherapy against hematological cancers for more than six decades. Its therapeutic efficacy relies on the cytoreductive effects of the conditioning regimen but also on potent graft- versus -tumor (GVT) reactions mediated by donor-derived immune cells. However, beneficial GVT effects may be counterbalanced by acute GVHD (aGVHD), a systemic syndrome in which donor immune cells attack healthy tissues of the recipient, resulting in severe inflammatory lesions mainly of the skin, gut, and liver. Despite standard prophylaxis regimens, aGVHD still occurs in approximately 20–50% of alloHCT recipients and remains a leading cause of transplant-related mortality. Over the past two decades, advances in the understanding its pathophysiology have helped to redefine aGVHD reactions and clinical presentations as well as developing novel strategies to optimize its prevention. In this review, we provide a brief overview of current knowledge on aGVHD immunopathology and discuss current approaches and novel strategies being developed and evaluated in clinical trials for aGVHD prevention. Optimal prophylaxis of aGVHD would prevent the development of clinically significant aGVHD, while preserving sufficient immune responsiveness to maintain beneficial GVT effects and immune defenses against pathogens. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM) is a haematological malignancy caused by malignant proliferation of plasma cells in bone marrow. In recent years, MM patients are commonly treated with chemotherapy, autologous stem cell transplantation, protease inhibitors, immunomodulatory drugs and monoclonal antibodies, however most patients eventually relapse. Therefore, more effective therapies are highly needed. Anti‐BCMA CAR‐T therapy, a novel and efficacious method for treating MM and relapsed/refractory multiple myeloma (RRMM), has been designed and applied in clinics. The CAR‐T can specifically recognize the targeted molecule B cell maturation antigen (BCMA) and kill MM cells expressing BCMA and several clinical trials have revealed high response rates in the therapy. Herein, we summarize the developments, the current design and clinical trials, the side effects of anti‐BCMA CAR‐T therapy and comparison of it with other CAR‐T therapies. [ABSTRACT FROM AUTHOR]

Allogeneic stem cell transplantation (allo-SCT) represents the most beneficial treatment for patients with active relapsed/refractory (R/R) hematologic malignancies. Recently, sequential regimens combining debulking chemotherapy followed by reduced-intensity conditioning (RIC) have shown encouraging results for these patients. In this retrospective study, we report the extended results of a sequential regimen of clofarabine, cytosine arabinoside, and RIC in 131 adults with active R/R myeloid disease at transplant. Conditioning consisted of clofarabine (30 mg/m2/day) and cytosine arabinoside (1 g/m2/day) for 5 days, followed, after a rest of 3 days, by an RIC combining cyclophosphamide (60 mg/kg) for 1 day, iv busulfan (3.2 mg/kg/day) for 2 days, and anti-thymocyte globulin (2.5 mg/kg/day) for 2 days. Between 2007 and 2016, 131 patients (males n = 75, median age: 52.6 years) were identified from the SFGM-TC registry. There were 111 acute myeloid leukemia (AML) patients and 20 cases with myelodysplastic or myeloproliferative syndrome. Status at transplant was known for all but 4 patients and was primary refractory (n = 81) and 1st or 2nd relapse (n = 46). All patients received allo-SCT from a matched donor (sibling n = 64, unrelated n = 67). Engraftment was observed in 105/122 (86%) evaluable cases and 63% of the patients achieved complete remission (CR) after transplant. The 1-year overall survival, disease-free survival, relapse incidence, non-relapse mortality, and graft-versus-host disease-free/relapse-free survival were 39.2%, 28.1%, 41.0%, 30.8%, and 22.2%, respectively. This study confirms that this sequential clofarabine-based regimen provides a high CR rate in this critical population, although relapse remains a matter of concern. [ABSTRACT FROM AUTHOR]

T cells in grafts serve an important role in the pathogenesis of graft versus host disease (GVHD) and immune recovery during HLA matched allogeneic stem cell transplantation. However, the role of T cells in the haploidentical peripheral blood stem cell transplantation (Haplo-PBSCT) is yet to be determined. In the present study, the role of CD3+ T cells in grafts and impact on hematopoietic and immune recovery, cytomegalovirus (CMV) reactivation, GVHD, relapse, progress free survival and overall survival (OS) were evaluated and analyzed. A total of 30 patients who underwent haplo-PBSCT were included in the present study. CD3+ T cells accounted for a median of 23.1% (range 8-47.4%) with a median dose of 299.7x106/kg (range 104-623.4). Patients were divided into two groups according to the CD3+ T cell count: Above the median (high T cell group) and below the median CD3+ T cell (low T cell group). No significant difference was identified between neutrophil and platelet recovery time between two groups (P>0.05). The mean lymphocyte recovery time of high T cell group and low T cell group were 107.07 days (95% CI 79.88-134.25), and 50.4 days (95% CI 41.42-59.38), respectively. The lymphocyte recovery time of high T cell group was higher that of low T cell group (P<0.05). No significant difference between CMV reactivation, chronic GVHD and primary disease relapse rates was observed between two groups (P>0.05). The cumulative incidence of grade II or above acute GVHD was higher in the high T groups compared with low T groups (P<0.05). The overall survival and progress free survival rates were higher in the low T cell group compared with the high T cell group (P<0.05). In conclusion, high levels of CD3+ T cells in the grafts were associated with delayed lymphocyte recovery and an increased risk of acute GVHD and decreased overall survival. [ABSTRACT FROM AUTHOR]

Summary: Acute myeloid leukaemia (AML) with t(6;9)(p23;q34) is a poor‐risk entity, commonly associated with FLT3‐ITD (internal tandem duplication). Allogeneic stem‐cell tranplantation (allo‐SCT) is recommended, although studies analysing the outcome of allo‐SCT in this setting are lacking. We selected 195 patients with t(6;9) AML, who received a first allo‐SCT between 2000 and 2016 from the EBMT (European Society for Blood and Marrow Transplantation) registry. Disease status at time of allo‐SCT was the strongest independent prognostic factor, with a two‐year leukaemia‐free survival and relapse incidence of 57% and 19% in patients in CR1 (first complete remission), 34% and 33% in CR2 (second complete remission), and 24% and 49% in patients not in remission, respectively (P < 0·001). This study, which represents the largest one available in t(6;9) AML, supports the recommendation to submit these patients to allo‐SCT in CR1. [ABSTRACT FROM AUTHOR]

The influence of peripheral blood stem cell (PBSC) graft cell contents after transplant with post-transplant cyclophosphamide (PTCY) remains unclear. Here, we retrospectively report on a cohort of 77 adults who received a Baltimore-based reduced-intensity conditioning regimen either with fludarabine (n = 40) or clofarabine (n = 37) and PTCY. With a median follow-up of 29.2 months, [2-]year overall (OS), disease-free (DFS), and GVHD/relapse-free survival (GRFS) rates were 62.8%, 51%, and 36.7%, respectively. The incidence of grades [2-]4 acute GVHD was significantly higher in patients transplanted with a haplodonor (n = 56), at 57.1% vs 19% (p = 0.006). PBSC graft cell contents (CD45+, CD34+, and CD3+ cells) had no impact on any outcome. Considering immune reconstitution until 1 year, only monocytes were above the normal range (as early as day + 30) during the first year post-transplant. In multivariate analysis, an older donor (> 45 years) and a high/very high disease risk index were independently associated with lower OS. A higher monocyte count (> median) at day + 90 was also associated with better OS, DFS, and GRFS. Donor/recipient CMV status matching was independently associated with GRFS. In conclusion, our data support the fact that there is no need to manipulate the graft before infusion in the particular context of PBSC/PTCY Baltimore-based allotransplant. [ABSTRACT FROM AUTHOR]

Introduction: Secondary haemophagocytic lymphohistiocytosis (sHLH) or Macrophage Activation Syndrome (MAS) is a life-threatening hyperinflammatory syndrome that can occur in patients with severe infections, malignancy or autoimmune diseases. It is also a rare complication of haematopoetic stem cell transplantation (HSCT), with a high mortality. It may be associated with graft vs. host disease in the allogeneic HSCT setting. It is also reported following CAR-T cell therapy, but differentiation from cytokine release syndrome (CRS) is challenging. Here, we summarise the literature and present results of a survey of current awareness and practice in EBMT-affiliated centres of sHLH/MAS following HSCT and CAR-T cell therapy. Methods: An online questionnaire was sent to the principal investigators of all EBMT member transplant centres treating adult patients (18 years and over) inviting them to provide information regarding: number of cases of sHLH/MAS seen in their centre over 3 years (2016–2018 inclusive); screening strategies and use of existing diagnostic/classification criteria and treatment protocols. Results: 114/472 centres from 24 different countries responded (24%). We report estimated rates of sHLH/MAS of 1.09% (95% CI = 0.89–1.30) following allogeneic HSCT, 0.15% (95% CI = 0.09–5.89) following autologous HSCT and 3.48% (95% CI = 0.95–6.01) following CAR-T cell therapy. A majority of centres (70%) did not use a standard screening protocol. Serum ferritin was the most commonly used screening marker at 78% of centres, followed by soluble IL-2 receptor (24%), triglycerides (15%), and fibrinogen (11%). There was significant variation in definition of "clinically significant" serum ferritin levels ranging from 500 to 10,000 μg/mL. The most commonly used criteria to support diagnosis were HLH-2004 (43%) and the H score (15%). Eighty percent of responders reported using no standard management protocol, but reported using combinations of corticosteroids, chemotherapeutic agents, cytokine blockade, and monoclonal antibodies. Conclusions: There is a remarkable lack of consistency between EBMT centres in the approach to screening, diagnosis and management. Further research in this field is needed to raise awareness of and inform harmonised, evidence-based approaches to the recognition and treatment of sHLH/MAS following HSCT/CAR-T cell therapy. [ABSTRACT FROM AUTHOR]

Post-transplant cyclophosphamide (PTCy) has been explored in several types of stem cell transplantations (SCTs) and it proved highly effective in controlling graft-versus-host disease (GvHD) without aggravating relapsed disease. However, PTCy alone has resulted in inferior outcomes in matched sibling donor (MSD) employing peripheral blood (PB) SCTs. We hypothesized that adding thymoglobulin to PTCy would be able to control GvHD effectively. We retrospectively compared the use of standard GvHD prophylaxis encompassing a combination of PTCy and thymoglobulin (ATG) in patients with myeloid malignancies in a myeloablative conditioning MSD PBSCT. Forty-two patients underwent PBSCT using either methotrexate and cyclosporine (MTX/CSA, 21 patients) or PTCy and ATG (21 patients) as a GvHD prophylaxis. With median follow-ups of 71 months, the 1-year GvHD-free, relapse-free survival rates and chronic GvHD-free survival rate of the standard and PTCy/ATG groups were similar: 24% versus 37% (P = 0.251) and 29% versus 43% (P = 0.095), respectively. When focusing on chronic GvHD we observed that 17/35 patients (48.6%) suffered from this, 5/18 (27.8%) treated with MTX/CSA had extensive chronic GvHD, but 0/17 PTCy/ATG did. Twenty-one patients required additional GvHD treatment; 7/21 in the PTCy/ATG received only corticosteroid, while 8/14 MTX/CSA required at least 2 drugs. The 5-year overall survival rates were 52% and 52% (P = 0.859), and the 5-year disease-free survival rates were 52% and 52% (P = 0.862) for the MTX/CSA and PTCy/ATG groups, respectively. We conclude that PTCy in combination with ATG without immunosuppression of a calcineurin inhibitor can effectively control GvHD. [ABSTRACT FROM AUTHOR]

Patients with prolonged isolated thrombocytopenia (PT) after allogeneic stem cell transplantation (allo-SCT) are known to have a poor prognosis. However, there is no standard treatment for PT. The present study aimed to investigate the potential effect of a novel recombinant human thrombopoietin (rhTPO) in a cohort of patients with PT following allo-SCT. A total of 24 patients with PT (including delayed platelet engraftment and secondary failure of platelet recovery) were treated with rhTPO from July 1, 2016 to May 31, 2017. rhTPO injections were administered at 300 IU/kg/d for 28 consecutive days or until platelet counts were ≥ 50 × 109/L, independent of platelet transfusion. Response was defined as platelet recovery to ≥ 20 × 109/L for seven consecutive days without transfusion support during or within 7 days of the end of rhTPO treatment. All patients completed the 28 days of treatment, and none were withdrawn due to adverse effects. The overall response was 45.8%, which was significantly higher than historical data (12.2%, p < 0.001). The median response time was 12 (7–25) days from the initiation of rhTPO treatment. A response to rhTPO was associated with megakaryocytes in the bone marrow (positive vs. negative, 81.8 vs. 22.2%; p = 0.022). Among 11 patients exhibiting a response to rhTPO, the median number of megakaryocytes in bone marrow was increased significantly (10 vs. 2; p = 0.036) after rhTPO treatment. In conclusion, the results of this preliminary study suggest that rhTPO may represent a therapeutic option, with a response of 45.8% for patients with PT after allo-SCT, and especially for those with megakaryocytes in the bone marrow. However, this should be further confirmed in randomized prospective clinical trials. [ABSTRACT FROM AUTHOR]

Allogeneic hematopoietic stem cell transplantation (allo-SCT) is the most established and commonly used cellular immunotherapy in cancer care. It is the most potent anti-leukemic therapy in patients with acute myeloid leukemia (AML) and is routinely used with curative intent in patients with intermediate and poor risk disease. Donor T cells, and possibly other immune cells, eliminate residual leukemia cells after prior (radio)chemotherapy. This immune-mediated response is known as g raft-versus- l eukemia (GvL). Donor alloimmune responses can also be directed against healthy tissues, which is known as g raft-versus- h ost d isease (GvHD). GvHD and GvL often co-occur and, therefore, a major barrier to exploiting the full immunotherapeutic benefit of donor immune cells against patient leukemia is the immunosuppression required to treat GvHD. However, curative responses to allo-SCT and GvHD do not always occur together, suggesting that these two immune responses could be de-coupled in some patients. To make further progress in successfully promoting GvL without GvHD, we must transform our limited understanding of the cellular and molecular basis of GvL and GvHD. Specifically, in most patients we do not understand the antigenic basis of immune responses in GvL and GvHD. Identification of antigens important for GvL but not GvHD, and vice versa, could impact on donor selection, allow us to track GvL immune responses and begin to specifically harness and strengthen anti-leukemic immune responses against patient AML cells, whilst minimizing the toxicity of GvHD. [ABSTRACT FROM AUTHOR]

Summary: Graft‐versus‐host disease (GVHD) is a major cause of transplant‐related mortality (TRM) after allogeneic haematopoietic stem cell transplantation (HSCT) and presents a challenge in haploidentical HSCT. GVHD may be prevented by ex vivo graft T‐cell depletion or in vivo depletion of proliferating lymphocytes. However, both approaches pose significant risks, particularly infections and relapse, compromising survival. A photodepletion strategy to eliminate alloreactive T cells from mismatched donor lymphocyte infusions (enabling administration without immunosuppression), was used to develop ATIR101, an adjunctive therapy for use after haploidentical HSCT. In this phase I dose‐finding study, 19 adults (median age: 54 years) with high‐risk haematological malignancies were treated with T‐cell‐depleted human leucocyte antigen‐haploidentical myeloablative HSCT followed by ATIR101 at doses of 1 × 104–5 × 106 CD3+ cells/kg (median 31 days post‐transplant). No patient received post‐transplant immunosuppression or developed grade III/IV acute GVHD, demonstrating the feasibility of ATIR101 infusion for evaluation in two subsequent phase 2 studies. Additionally, we report long‐term follow ‐up of patients treated with ATIR101 in this study. At 1 year, all 9 patients receiving doses of 0·3–2 × 106 CD3+ cells/kg ATIR101 remained free of serious infections and after more than 8 years, TRM was 0%, relapse‐related mortality was 33% and overall survival was 67% in these patients. [ABSTRACT FROM AUTHOR]