Prospective Randomized Study Comparing Myeloablative Unrelated Umbilical Cord Blood Transplantation versus HLA-Haploidentical Related Stem Cell Transplantation for Adults with Hematologic Malignancies.

In this prospective randomized study, we compared the outcomes of single-unit umbilical cord blood transplantation (UCBT) and unmanipulated haploidentical stem cell transplantation (haplo-SCT) with post-transplantation cyclophosphamide (PTCy) in adults with hematologic malignancies. All patients received a myeloablative conditioning (MAC) regimen consisting of thiotepa, busulfan, and fludarabine, with antithymocyte globulin (ATG) added for UCBT recipients. Nineteen patients were randomized to UCBT and the other 26 to haplo-HSCT. Four patients (15%) allocated to the haplo-HSCT arm lacked a suitable donor and were crossed over to the UCBT arm. Finally, 23 underwent UCBT and 22 underwent haplo-HSCT. The cumulative incidence of neutrophil recovery was 87% at a median of 19 days (range, 13 to 24 days) in the UCBT arm versus 100% at a median of 17 days (range, 13 to 25 days) in the haplo-SCT arm (P = .04). Platelet recovery was 70% at a median of 40 days (range, 18 to 129 days) in the UCBT arm versus 86% at a median of 24 days (range, 12 to 127 days) in the haplo-HCT arm (P = .02). Rates of acute graft-versus-host disease (GVHD) grade II-IV or grade III-IV, overall chronic GVHD, and extensive chronic GVHD in the UCBT and Haplo-SCT arms were 43% versus 36% (P = .8), 9% versus 9% (P = 1), 66% versus 43% (P = .04), and 41% versus 23% (P = .2), respectively. Two-year nonrelapse mortality and relapse in the 2 arms were 52% versus 23% (P = .06) and 17% versus 23% (P = .5), respectively. Two-year disease-free survival, overall survival, and GVHD/relapse-free survival in the 2 arms were 30% versus 54% (P = .2), 35% versus 59% (P = .1), and 17% versus 40% (P = .04), respectively. Our data show that in the context of an MAC regimen, haplo-SCT with PTCy provides improved outcomes compared with ATG-containing single-unit UCBT.

Predicting Survival after Allogeneic Hematopoietic Cell Transplantation in Myelofibrosis: Performance of the Myelofibrosis Transplant Scoring System (MTSS) and Development of a New Prognostic Model.

Accurate prognostic tools are crucial to assess the risk/benefit ratio of allogeneic hematopoietic cell transplantation (allo-HCT) in patients with myelofibrosis (MF). We aimed to evaluate the performance of the Myelofibrosis Transplant Scoring System (MTSS) and identify risk factors for survival in a multicenter series of 197 patients with MF undergoing allo-HCT. After a median follow-up of 3.1 years, 47% of patients had died, and the estimated 5-year survival rate was 51%. Projected 5-year risk of nonrelapse mortality and relapse incidence was 30% and 20%, respectively. Factors independently associated with increased mortality were a hematopoietic cell transplantation-specific comorbidity index (HCT-CI) ≥3 and receiving a graft from an HLA-mismatched unrelated donor or cord blood, whereas post-transplant cyclophosphamide (PT-Cy) was associated with improved survival. Donor type was the only parameter included in the MTSS model with independent prognostic value for survival. According to the MTSS, 3-year survival was 62%, 66%, 37%, and 17% for low-, intermediate-, high-, and very high-risk groups, respectively. By pooling together the low- and intermediate-risk groups, as well as the high- and very high-risk groups, we pinpointed 2 categories: standard risk and high risk (25% of the series). Three-year survival was 62% in standard-risk and 25% in high-risk categories (P < .001). We derived a risk score based on the 3 independent risk factors for survival in our series (donor type, HCT-CI, and PT-Cy). The corresponding 5-year survival for the low-, intermediate-, and high-risk categories was 79%, 55%, and 32%, respectively (P < .001). In conclusion, the MTSS model failed to clearly delineate 4 prognostic groups in our series but may still be useful to identify a subset of patients with poor outcome. We provide a simple prognostic scoring system for risk/benefit considerations before transplantation in patients with MF.

Posaconazole salvage therapy: The Posifi study.

BACKGROUND: Posaconazole (PCZ) is used mainly for the prevention of invasive fungal infection (IFI). METHODS: A multicentre retrospective, investigational study using a non-randomized, single-arm design carried out in six tertiary hospitals in Spain to evaluate the use of PCZ in different forms of administration in the (non-prophylactic) treatment of IFI. RESULTS: Over an eight-year-period, 67 patients were included in this study. PCZ was administered as salvage therapy (intolerant or refractory to a previous antifungal agent) in 65/67 (97%); of these, it was used against Aspergillosis (68.6%), Zygomycosis (13.4%), other moulds (8.9%) and yeast (10.5%). The median duration of PCZ therapy was 75 days. The oral solution was associated with low serum levels (<0.7 mg/L) in 63% of available patients. Clinical response at 3 and 12 months of PCZ therapy were for aspergillosis: 47.8% and 41.3%; for zygomycosis: 55.5% and 55.5%; and for other mycoses: 69.2% and 69.2%, respectively. Suspension by toxicity was only observed in 6% and 7.5% of patients at 3 and 12 months, respectively, mainly with grade III/IV elevations of liver function test (LFTs). CONCLUSIONS: Posaconazole salvage therapy, especially oral tablets, can be an effective alternative option for patients with IFI who cannot tolerate or do not respond to other antifungal therapies.

Umbilical cord blood transplantation in adults with advanced hodgkin's disease: high incidence of post-transplant lymphoproliferative disease.

We report the outcome of 30 consecutive patients with Hodgkin disease (HD) who underwent single-unit UCBT. Most (90%) patients had failed previous autologous hematopoietic stem cell transplantation. The conditioning regimens were based on combinations of thiotepa, busulfan, cyclophosphamide or fludarabine, and antithymocyte globulin. The cumulative incidence (CI) of myeloid engraftment was 90% [95% confidence interval (C.I.), 74-98%] with a median of 18 d (range, 10-48). CI of acute graft-versus-host disease (GvHD) grades II-IV was 30% (95% C.I., 17-44%), while the incidence of chronic GVHD was 42% (95% C.I., 23-77%). The non-relapse mortality (NRM) at 100 d and 4 yr was 30% (95% C.I., 13-46%) and 47% (95% C.I., 29-65%), respectively. EBV-related post-transplant lymphoproliferative disease (EBV-PTLD) accounted for more than one-third of transplant-related death, with an estimate incidence of 26% (95% C.I., 9-44). The incidence of relapse at 4 yr was 25% (95% C.I., 9-42%). Four-year event-free survival (EFS) and overall survival (OS) were 28% and 30%, respectively. Despite a high NRM and an unexpected high incidence of EBV-PTLD, UCBT in heavily pretreated HD patients is an option for patients lacking a suitable adult donor, provided the disease is not in refractory relapse.

Imatinib and dasatinib as salvage therapy for sclerotic chronic graft-vs-host disease.

AIM: To assess the toxicity, tolerance, steroid-sparing capacity, effectiveness, and response rate to imatinib and dasatinib for the treatment of severe sclerotic chronic graft-vs-host disease (scGVHD). METHODS: This retrospective study analyzed 8 consecutive patients with severe refractory scGVHD who received salvage therapy with imatinib. Patients intolerant and/or refractory to imatinib received dasatinib treatment. RESULTS: 7 patients discontinued imatinib treatment (1 achieved complete response, 5 were resistant and/or intolerant, and 1 developed grade IV neutropenia) and 1 patient achieved prolonged partial response, but died due to an infectious complication while on treatment. 5 patients started dasatinib treatment (3 achieved partial responses and discontinued dasatinib, 1 achieved a durable partial response, but died due to a consecutive rapid pulmonary cGVHD progression and 1 with stable disease discontinued treatment due to gastroenteric intolerance). The response rate (partial and/or complete responses) for severe scGVHD was 25% for imatinib and 60% for dasatinib. CONCLUSION: In our series, dasatinib was better tolerated, safer, steroid-sparing, and had a low incidence of infectious complications, which suggests that it may be a more effective therapeutic alternative for patients with refractory scGVHD than imatinib. Treatment of scGVHD with effective antifibrotic drugs such as TKI, which block the kinase fibrotic pathway, may be a safe and effective therapeutic option, but further studies are needed to confirm our findings.

Serum galactomannan versus a combination of galactomannan and polymerase chain reaction-based Aspergillus DNA detection for early therapy of invasive aspergillosis in high-risk hematological patients: a randomized controlled trial.

BACKGROUND: The benefit of the combination of serum galactomannan (GM) assay and polymerase chain reaction (PCR)-based detection of serum Aspergillus DNA for the early diagnosis and therapy of invasive aspergillosis (IA) in high-risk hematological patients remains unclear. METHODS: We performed an open-label, controlled, parallel-group randomized trial in 13 Spanish centers. Adult patients with acute myeloid leukemia and myelodysplastic syndrome on induction therapy or allogeneic hematopoietic stem cell transplant recipients were randomized (1:1 ratio) to 1 of 2 arms: "GM-PCR group" (the results of serial serum GM and PCR assays were provided to treating physicians) and "GM group" (only the results of serum GM were informed). Positivity in either assay prompted thoracic computed tomography scan and initiation of antifungal therapy. No antimold prophylaxis was permitted. RESULTS: Overall, 219 patients underwent randomization (105 in the GM-PCR group and 114 in the GM group). The cumulative incidence of "proven" or "probable" IA (primary study outcome) was lower in the GM-PCR group (4.2% vs 13.1%; odds ratio, 0.29 [95% confidence interval, .09-.91]). The median interval from the start of monitoring to the diagnosis of IA was lower in the GM-PCR group (13 vs 20 days; P = .022), as well as the use of empirical antifungal therapy (16.7% vs 29.0%; P = .038). Patients in the GM-PCR group had higher proven or probable IA-free survival (P = .027). CONCLUSIONS: A combined monitoring strategy based on serum GM and Aspergillus DNA was associated with an earlier diagnosis and a lower incidence of IA in high-risk hematological patients. Clinical Trials Registration. NCT01742026.

Intermediate doses of cytarabine plus granulocyte-colony-stimulating factor as an effective and safe regimen for hematopoietic stem cell collection in lymphoma patients with prior mobilization failure.

BACKGROUND: High-dose chemotherapy supported by autologous stem cell transplantation (ASCT) is an effective treatment for patients with lymphomas. However, failure to reach the minimum threshold of hematopoietic stem cells to proceed to ASCT may occur, even with the most effective strategies currently available. STUDY DESIGN AND METHODS: We report on 33 patients diagnosed with lymphoma who had at least one prior mobilization failure and received cytarabine at a dose of 400 mg/m(2) /day intravenously × 3 days plus granulocyte-colony-stimulating factor (G-CSF) 10 to 12 µg/kg/day as mobilization regimen. The median number of previous lines of chemotherapy was three. RESULTS: Thirty-two of 33 patients (96.8%) reached the target CD34+ cell dose (>2 × 10(6) /kg). The mean (range) number of apheresis procedures was 1.8 (1-3) with 4.69 × 10(6) (1.5 × 10(6) -6.8 × 10(6) )/kg CD34+ cells obtained. All but one patient received chemomobilization in the outpatient department. Severe infections or treatment-related mortality were not observed. All patients that received ASCT (31/33) engrafted without requiring G-CSF during the posttransplant period. CONCLUSION: This study shows that cytarabine at intermediate doses plus G-CSF in patients diagnosed with lymphoma who had a prior mobilization failure is a feasible and effective mobilization regimen.

Sequential third-party mesenchymal stromal cell therapy for refractory acute graft-versus-host disease.

We evaluated the feasibility, safety, and efficacy of the administration of 4 sequential doses (intravenously administered on days 1, 4, 11, and 18) of cryopreserved bone marrow-derived mesenchymal stromal cells (MSC) expanded with platelet lysate and obtained from third-party donors as a second-line treatment for steroid-refractory acute graft-versus-host (aGVHD) disease in a series of 25 patients. All patients received at least 2 doses of MSC, whereas 21 received 3 doses and 18 received the initially planned 4 doses. Because of the achievement of partial response, 4 patients received additional doses of MSC. Median single cell dose administered was 1.1 × 10(6) MSC/kg of recipient body weight. There were no adverse events related to the MSC infusion in the 99 procedures performed, with the exception of a cardiac ischemic event that occurred twice in a patient with prior history of cardiac ischemia. Response to MSC at 60 days after the first dose was evaluable in 24 patients. Seventeen patients (71%) responded (11 complete and 6 partial responses), with a median time to response of 28 days after the first MSC dose, whereas 7 patients did not respond. In summary, we can conclude that sequential cryopreserved third-party MSC therapy administered on days 1, 4, 11, and 18 is a safe procedure for patients with steroid-refractory aGVHD. This strategy may provide a high rate of overall responses of aGVHD with a low toxicity profile.

Post-transplant cyclophosphamide compared to sirolimus/tacrolimus in reduced intensity conditioning transplants for patients with lymphoid malignancies.

Despite novel cellular and immunomodulatory therapies, allogeneic hematopoietic stem cell transplantation (HSCT) remains a treatment option for lymphoid malignancies. Post-transplant cyclophosphamide (PTCY) is increasingly employed for graft vs. host disease (GVHD) prophylaxis. This study aims to evaluate the safety and efficacy of PTCY in reduce intensity (RIC) HSCT for patients with lymphoid neoplasms compared to sirolimus with tacrolimus (SIR/TAC). The primary endpoint was to compare grade III-IV acute GVHD, severe chronic GVHD, and relapse-free survival (GRFS) between the two GVHD prophylaxis strategies. This study, conducted from January 2012 to December 2020, included 171 consecutive patients (82 in the PTCY and 89 in the SIR/TAC group). Results revealed a significantly decreased incidence of moderate and severe forms of chronic GVHD in PTCY cohort (5.8% [95% CI, 1.8 to 13.1]) versus the SIR/TAC cohort (39.6% [95% CI, 29.3 to 49.7] (p < 0.001)). Other outcomes, including GRFS (PTCY [45.9% (95% CI, 35.8-58.7)] and SIR/TAC groups [36.8% (95% CI, 28-48.4)], (p = 0.72)), non-relapse mortality (NRM), relapse and overall survival (OS) were similar in both groups. Interestingly, the failure to achieve GRFS was mainly attributed to GVHD in the SIR/TAC group, while disease relapse was the primary reason in the PTCY cohort.

Real-World Experience with Isavuconazole in Allogeneic Stem Cell Transplantation in Spain.

Invasive fungal infections (IFI) pose a significant complication after hematopoietic stem cell transplantation (HSCT). Isavuconazole (ISV) is a new generation azole with a favourable adverse effect and interaction profile approved for the treatment of invasive aspergillosis and mucormycosis. We analyzed the indications, effectiveness, adverse event profile and drug interaction management of ISV in the real-world setting in adults who received allogeneic-HSCT (allo-HSCT) within the Spanish Group of HSCT and Cell Therapy (GETH-TC). We conducted a multicenter retrospective study of all consecutive adult allo-HSCT recipients (≥18 years) who received ISV either for IFI treatment or prophylaxis, from December 2017 to August 2021, in 20 centers within the Spanish Group of Hematopoietic Stem Cell Transplantation and Cell Therapy (GETH-TC). A total of 166 adult allografted patients who received ISV from 2017 to 2021 were included. Median age was 48 years with 43% females. In 81 (49%) patients, ISV was used for treatment of IFI, and in 85 (51%) for prophylaxis. Median duration of ISV administration for IFI treatment was 57 days (range 31-126) and 86 days (range 33-196) for prophylaxis. Most frequent indication for treatment was invasive aspergillosis (78%), followed by mucormycosis (6%). Therapeutic success (45%) was the most frequent reason for ISV withdrawal. In the prophylaxis group, the resolution of IFI risk factors was the most frequent reason for withdrawal (62%). Six (7%) breakthrough IFI were reported. The majority of patients (80%) presented pharmacologic interactions. Twenty-one patients (13%) reported adverse events related to ISV, mainly liver biochemistry abnormalities, which led to ISV withdrawal in 7 patients (4%). ISV was effective and well tolerated for IFI treatment and prophylaxis, with a manageable interaction profile.

The combination of sirolimus plus tacrolimus improves outcome after reduced-intensity conditioning, unrelated donor hematopoietic stem cell transplantation compared with cyclosporine plus mycofenolate.

Different types of graft-versus-host disease prophylaxis have been proposed in the setting of reduced intensity and non-myeloablative allogeneic stem cell transplantation. An alternative combination with sirolimus and tacrolimus has recently been tested although comparative studies against the classical combination of a calcineurin inhibitor and mycophenolate mofetil or methotrexate are lacking. We describe the results of a prospective, multicenter trial using sirolimus + tacrolimus as immunoprophylaxis, and compare this approach with our previous experience using cyclosporine + mycophenolate in the setting of unrelated donor transplantation setting after reduced-intensity conditioning. Forty-five patients received cyclosporine + mycophenolate between 2002 and mid-2007, while the subsequent 50 patients, who were transplanted from late 2007, were given sirolimus + tacrolimus. No significant differences were observed in terms of hematopoietic recovery or acute graft-versus-host disease overall, although gastrointestinal acute graft-versus-host disease grade ≥ 2 was more common in the cyclosporine + mycophenolate group (55% versus 21%, respectively, P=0.003). The 1-year cumulative incidence of chronic graft-versus-host disease was 50% versus 90% for the patients treated with the sirolimus- versus cyclosporine-based regimen, respectively (P<0.001), while the incidence of extensive chronic disease was 27% versus 49%, respectively (P=0.043). The 2-year non-relapse mortality rate was 18% versus 38% for patients receiving the sirolimus- versus the cyclosporine-based regimen, respectively (P=0.02). The event-free survival and overall survival at 2 years were 53% versus 29% (P=0.028) and 70% versus 45% (P=0.018) among patients receiving the sirolimus- versus the cyclosporine-based regimen, respectively. In conclusion, in the setting of reduced intensity transplantation from an unrelated donor, promising results can be achieved with the combination of sirolimus + tacrolimus, due to a lower risk of chronic graft-versus-host disease and non-relapse mortality, which translates into better event-free and overall survival rates, in comparison with those achieved with cyclosporine + mycophenolate.

To freeze or not to freeze peripheral blood stem cells prior to allogeneic transplantation from matched related donors.

BACKGROUND: The standard practice in allogeneic stem cell transplant (alloSCT) is to infuse peripheral blood stem cells (PBSC) the same day or the day after collection once the patient has received conditioning regimen. To obtain and freeze PBSC prior to SCT would be desirable to get a better logistic and to confirm the quality of the product. Unfortunately, studies comparing both approaches are lacking. AIM: In this retrospective study, we analyze the impact of using fresh (N: 107) or previously frozen PBSC (N: 224) on overall outcomes among patients consecutively undergoing alloPBSCT from a matched related donor. RESULTS: Granulocyte engraftment (>500/mcl × 3 days) was faster in the frozen group (14 vs. 16 days, respectively; P = 0.001), while no significant differences on platelet recovery were observed. Patients receiving frozen PBSC had a higher incidence of global acute graft-versus-host disease (aGVHD) (63 vs. 44%, P < 0.001) mostly involving skin and had an earlier onset (13 vs. 30 days, P < 0.001). Response to first-line treatment with corticoids was similar in both groups. No statistically significant differences were found regarding overall chronic GVHD (58 vs. 66%) nor global survival (44 vs 48%), disease-free survival (39 vs. 33%), non-relapse mortality (24 vs. 16% at 1 year), and relapse rates in the frozen vs. fresh group, respectively. CONCLUSIONS: Infusion of previously frozen stem cells may achieve similar overall outcomes compared to fresh infusion, allowing to program donor apheresis and transplantation. However, cryopreservation might influence on the different pattern of aGVHD, issue that deserves further studies.

Allogeneic Hematopoietic Stem Cell Transplantation in Transformed Follicular Lymphoma (tFL): Results of a Retrospective Multicenter Study from GELTAMO/GETH-TC Spanish Groups.

BACKGROUND: Transformation of follicular lymphoma into an aggressive lymphoma (tFL) worsens the prognosis and the standard treatment is not completely defined. Allogeneic hematopoietic stem cell transplantation (alloSCT) could be a potentially curative option for these patients, but it has not been widely explored. METHODS: We designed a retrospective multicenter study to analyze the efficacy and toxicity of alloSCT in tFL patients and potential prognostic factors of survival. RESULTS: A total of 43 patients diagnosed with tFL who underwent alloSCT in 14 Spanish centers between January 2000 and January 2019 were included. Median age was 44 (31-67) years. After a median follow-up of 58 months, estimated 5-year overall survival (OS) and progression-free survival (PFS) were both 35%. Estimated 100-day and 1-year non-relapse mortality (NRM) were 20% and 34%, respectively. The type of conditioning regimen (3-year OS of 52% vs. 20%, respectively, for reduced-intensity vs. myeloablative conditioning) and development of chronic graft versus host disease (cGVHD) (3-year OS of 75% vs. 40%) were the only factors significantly associated with OS. The only variable with an independent association with OS was cGVHD (HR, 3.4; 95% CI, 1.2-9.6). CONCLUSIONS: Our results indicate that alloSCT continues to be a potentially curative option for patients with tFL.

Allogeneic Stem Cell Transplantation in Mantle Cell Lymphoma; Insights into Its Potential Role in the Era of New Immunotherapeutic and Targeted Therapies: The GETH/GELTAMO Experience.

Allo-SCT is a curative option for selected patients with relapsed/refractory (R/R) MCL, but with significant NRM. We present the long-term results of patients receiving allo-SCT in Spain from March 1995 to February 2020. The primary endpoints were EFS, OS, and cumulative incidence (CI) of NRM, relapse, and GVHD. We included 135 patients, most (85%) receiving RIC. After a median follow-up of 68 months, 5-year EFS and OS were 47 and 50%, respectively. Overall and CR rates were 86 and 80%. The CI of relapse at 1 and 3 years were 7 and 12%. NRM at day 100 and 1 year were 17 and 32%. Previous ASCT and Grade 3-4 aGVHD were associated with a higher NRM. Grade 3-4 aGVHD, donor type (mismatch non-related), and the time-period 2006-2020 were independently related to worse EFS. Patients from 1995-2005 were younger, most from HLA-identical sibling donors, and were pretreated less. Our data confirmed that allo-SCT may be a curative option in R/R MCL with low a CI of relapse, although NRM is still high, being mainly secondary to aGVHD. The arrival of new, highly effective and low toxic immunotherapeutic or targeted therapies inevitably will relegate allo-SCT to those fit patients who fail these therapies, far away from the optimal timing of treatment.

Is Post-Transplant Cyclophosphamide the New Methotrexate?

Introducing post-transplant, cyclophosphamide (PT-Cy) graft-versus-host disease (GVHD) prophylaxis in the setting of haploidentical donor transplantation has marked the most important advance in allogeneic hematopoietic cell transplantation (alloHCT) within the past 15 years. The efficacy of this procedure and its simple features have allowed for the significantly widespread application of alloHCT worldwide. Indeed, the procedure's effectiveness in reducing immunological complications in the haploidentical setting has even challenged the status quo use of calcineurin-inhibitor, methotrexate-based GVHD prophylaxis in the setting of HLA-identical donors. Currently, however, prospective clinical trials in support of PT-Cy-based GVHD prophylaxis in the HLA-matched setting are striving to resolve the matter of its potential role. This review will briefly report the overall outcomes of PT-Cy-based GVHD prophylaxis in the haploidentical setting and summarize results obtained in the HLA-identical field. We will present future perspectives at the end of the manuscript.

Synchronizing the use of allogeneic hematopoietic cell transplantation in checkpoint blockade therapy for Hodgkin lymphoma.

INTRODUCTION: The use of checkpoint blockade therapy (CBT) has shown impressive results for the treatment of relapsed/refractory Hodgkin lymphoma (cHL). The impact of CBT depends on the reversal of an exhausted T-cell immune phenotype and a consequential increase in the immunological, anti-tumor effect derived from a patient's adaptive immunity. As most patients with classical Hodgkin lymphoma will relapse during or after this treatment, clinicians often provide consolidation with allogeneic hematopoietic cell transplantation (alloHCT) in fit patients. However, the mechanisms responsible for CBT efficacy can also be those that increase the risk of immunological complications after alloHCT. AREAS COVERED: We carried out in-depth research on the current medical literature to report and discuss the mechanism of action of CBT within a cHL setting; clinical results of CBT in cHL setting pre-alloHCT and post-alloHCT; interactions between CBT and alloHCT; and further clinical considerations. EXPERT OPINION: Checkpoint blockade therapy is an effective strategy for relapsed/refractory cHL. Its use is associated with higher immunological toxicities when administered before or after alloHCT. Whenever alloHCT is planned, clinicians should follow international recommendations such as using post-transplant cyclophosphamide GVHD prophylaxis.

Pretransplantation EASIX predicts intensive care unit admission in allogeneic hematopoietic cell transplantation.

The Endothelial Activation and Stress Index (EASIX) is a laboratory-based prognosis index defined as creatinine × lactate dehydrogenase/platelets. When measured at pretransplantation evaluation (EASIX-PRE), it predicts allogeneic hematopoietic cell transplantation (alloHCT) mortality. This study explores its ability to predict intensive care unit (ICU) admission and validates EASIX-PRE predictive power for overall survival (OS) and nonrelapse mortality (NRM) in 167 consecutive patients undergoing alloHCT. EASIX-PRE was calculated retrospectively in all patients and transformed into log2 values (log2-EASIX-PRE). Log2-EASIX-PRE predicted ICU admission (hazard ratio [HR], 1.41; P < .001), OS (HR, 1.19; P = .011), and NRM (HR, 1.28; P = .004). The most discriminating EASIX-PRE cutoff value for risk of ICU admission was the 75th percentile (2.795); for OS and NRM, it was the median value (1.703). Patients with EASIX-PRE >2.795 had higher incidence of ICU admission in comparison with patients with lower EASIX-PRE values (day +180, 35.8% vs 12.8%; HR, 2.28; P = .010). Additionally, patients with EASIX-PRE >1.073 had lower OS (2 years, 57.7% vs 68.7%; HR, 1.98; P = .006) and higher NRM (2 years, 38.7% vs 18.5%; HR, 2.92; P = .001) than patients with lower EASIX-PRE results. Log2-EASIX-PRE was not associated with incidence of transplantation-associated microangiopathy, sinusoidal obstruction syndrome, or acute graft-versus-host disease. This study proposes EASIX-PRE as a prognostic tool to identify patients undergoing alloHCT at increased risk of severe organ dysfunction and who would therefore require ICU admission. Early identification of patients at high risk of severe events could contribute to personalized intervention design. Additionally, it validates the association between EASIX-PRE and OS and NRM in those undergoing alloHCT.

Severe infections and infection-related mortality in a large series of haploidentical hematopoietic stem cell transplantation with post-transplant cyclophosphamide.

Severe infections and their attributable mortality are major complications in recipients of allogeneic hematopoietic stem cell transplantation (alloSCT). We herein report 236 adult patients who received haploSCT with PTCy. The median follow-up for survivors was 37 months. The overall incidence of bloodstream infections by gram-positive and gram-negative bacteria at 37 months was 51% and 46%, respectively. The incidence of cytomegalovirus infection was 69%, while Epstein Barr virus infections occurred in 10% of patients and hemorrhagic cystitis in 35% of cases. Invasive fungal infections occurred in 11% at 17 months. The 3-year incidence of infection-related mortality was 19%. The median interval from transplant to IRM was 3 months (range 1-30), 53% of IRM occurred >100 days post-haploSCT. Risk factors for IRM included age >50 years, lymphoid malignancy, and developing grade III-IV acute GvHD. Bacterial infections were the most common causes of IRM (51%), mainly due to gram-negative bacilli BSI. In conclusion, severe infections are the most common causes of NRM after haploSCT with PTCy, with a reemergence of gram-negative bacilli as the most lethal pathogens. More studies focusing on the severe infections after haploSCT with PTCy and differences with other types of alloSCT in adults are clearly warranted.

Liquid biopsy for disease monitoring after anti-CD19 chimeric antigen receptor T cell in diffuse large B-cell lymphoma.

Objectives: Chimeric antigen receptor T cells (CARTs) against CD19 antigen represent an effective therapy for relapsed/refractory diffuse large B-cell lymphoma (rrDLBCL). There is no diagnostic test able to predict which patients with residual disease will relapse from those that will reach a delayed complete response. Positron emission tomography/computed tomography scan (PET-CT) is characterized by a significant number of false positive results after immunotherapy. Circulating tumor DNA (ctDNA) may be a good-useful tool to quantify minimal residual disease and for monitoring disease response. Methods: We present a patient with DLBCL treated with CART cells in which we tested the combined use of ctDNA and PET-CT scan. Results: Disease reassessment with PET-CT scan showed a partial remission (3 weeks) and a very good partial remission (2 months). A clinical progression at 3 months was confirmed with PET-CT scan. Levels of ctDNA progressively decreased and became undetectable. An initial increase in KMT2D p.E4385G variant allele frequency confirmed disease progression. Conclusions: Our case shows how the complementary use of ctDNA and PET-CT scan could be a helpful tool in the clinical management of these patients.

Analysis of Cell Subsets in Donor Lymphocyte Infusions from HLA Identical Sibling Donors after Allogeneic Hematopoietic Cell Transplant.

Donor lymphocytes infusions (DLIs) are a major therapeutic approach to treat relapse and mixed chimerism after allogeneic hematopoietic cell transplant (alloHCT). The impact of the composition regarding different cell subsets in the development of graft-versus-host disease (GVHD) is not fully understood. We performed a cell subsets analysis of 56 DLIs from fully HLA-compatible identical matched sibling donors (MSDs) in 36 alloHCT patients and studied its association with GVHD. A median of one DLI was infused per patient. Fourteen patients (38%) developed GVHD. The cell composition analysis of the first DLI (DLI1) showed that a high dose of B cells (P = .03) and CD27+ B cells (P < .01) was associated with GVHD. We identified DLI dose cutoff points for several cell populations above which GVHD was more frequent (CD8+ TN >3 × 106 cells/kg, CD27+ B cells >2.6 × 106/kg, CD27+ NK >0.35 × 106 cells/kg, and mononuclear cells >0.83 × 108/kg). Noteworthy, the proportion of CD4+ naive T cells (TN) or unselected TN was not linked with GVHD and a DLI1 containing a higher dose of regulatory T cells was not protective for GVHD. We studied several transplant clinical variables and did not find any association with GVHD. Altogether, this study provides a comprehensive analysis of the cell populations in a DLI from MSDs and identifies potential key cell subsets, which provides insight for the understanding of GVHD after DLI.