Outcomes and Long-Term Survival of Adolescent and Young Adult Patients Admitted to the Intensive Care Unit Following Allogeneic Hematopoietic Stem Cell Transplantation: A Single-Center Experience of 152 Patients.

BACKGROUND AND OBJECTIVES: Prognostic factors reliably predicting outcomes for critically ill adolescent and young adult (AYA) patients undergoing allogeneic hematopoietic cell transplantation (allo-HSCT) are lacking. We assessed transplant and intensive care unit (ICU)-related factors impacting patient outcomes. PATIENTS AND METHODS: AYA patients who underwent allo-HSCT and required ICU admission at a Tertiary care Centre, during the period of 2003-2013, were included in this retrospective review. This was a non-interventional study. Only outcomes after the first allo-HSCT and index ICU admissions were analyzed. Disease-, transplant-, and ICU-related variables were analyzed to identify risk factors predictive of survival. RESULTS: Overall, 152 patients were included (males, 60.5%); median age at transplantation was 24 years (interquartile range [IQR] 18-32.5); median age at admission to the ICU was 25.8 years (IQR 19-34). Eighty-four percent underwent transplantation for a hematological malignancy; 129 (85%) received myeloablative conditioning. Seventy-one percent of ICU admissions occurred within the first year after allo-HSCT. ICU admission was primarily due to respiratory failure (47.3%) and sepsis (43.4%). One hundred and three patients (68%) died within 28 days of ICU admission. The 1- and 5-year overall survival rates were 19% and 17%, respectively. Main causes for ICU-related death were refractory septic shock with multiorgan failure (n = 49, 32%) and acute respiratory distress syndrome (ARDS) (n = 39, 26%). Univariate analysis showed that ICU mortality was associated with an Acute Physiology and Chronic Health Evaluation (APACHE) II score >20, a sequential organ failure assessment (SOFA score) > 12, a high lactate level, anemia, thrombocytopenia, leukopenia, hyperbilirubinemia, a high international normalized ratio (INR) and acute graft-versus-host disease (GVHD). Multivariate analysis identified thrombocytopenia, high INR, and acute GVHD as independent predictors of mortality. CONCLUSIONS: In AYA allo-HSCT patients admitted to the ICU, mortality remains high. Higher SOFA and APACHE scores, the need for organ support, thrombocytopenia, coagulopathy, and acute GVHD predict poor outcomes.

Improved long-term survival rate in the responders to bortezomib, cyclophosphamide, dexamethasone induction therapy in a transplant-eligible cohort of predominantly middle-age multiple myeloma patients.

BACKGROUND: Multiple myeloma (MM) represents the second most common hematologic malignancy (15%). Induction with bortezomib, cyclophosphamide, and dexamthasone VCd (d: low dose dexamthasone) regimen is widely used due to its high effectiveness, low toxicity and good tolerability, particularly with renal impairment. Real-world data on the use of VCD in clinical practice is lacking. OBJECTIVES: Evaluate the real-world experience of the VCD regimen. DESIGN: Retrospective. SETTING: Tumor registry database of tertiary cancer care center. PATIENTS AND METHODS: newly diagnosed MM patients who received VCD induction and underwent autologous stem cell transplant (ASCT) from July 2007 to July 2020. MAIN OUTCOME MEASURES: response evaluation, progression-free survival (PFS) and overall survival (OS). SAMPLE SIZE: 87 patients. RESULTS: Of 102 patients who started induction with VCd, 87 patients experienced a partial response or more overall response rate of 85%). The median age of these 87 patients at diagnosis was 52 years, of which 29.9% presented with renal impairment and 60.3% of patients had stage 2 by the Revised International Staging System (R-ISS). Patients with a standard cytogenetic risk achieved a better response compared to those with a poor cytogenetic risk (P=.044). The post-induction response rates were 6.9% stringent complete remission (sCR), 35% complete remission (CR); 41.4% very good partial response (VGPR), and 16.1% partial response (PR), respectively; the response rates became greater for sCR and CR post-transplantation at day 100 with 16.1% sCR, 35.6% CR, 32.2% VGPR and 16.1% PR, respectively. The median PFS was 49 months and 5 years OS was 84%. PFS was better in patients who achieved sCR vs PR (83 vs 35 months, P=.037). High LDH, high-risk cytogenetic and stage 3 R-ISS showed a worse median PFS and OS. CONCLUSIONS: VCD induction in newly diagnosed MM is highly effective, convenient, tolerable and affordable regimen, especially in low and middle-income countries with limited resources, also with favorable outcomes and survival. while those who did not respond successfully shifted to VRD or VTD. LIMITATIONS: The usual limitations of a retrospective analysis using registry-level data, no data on quality of life.

Myeloablative Haploidentical Donor Hematopoietic Transplantation Using Post-Transplantation Cyclophosphamide and Antithymocyte Globulin.

Haploidentical donor (haplo-) hematopoietic stem cell transplantation (HSCT) with post-transplantation cyclophosphamide (PTCy) is now performed on a large scale worldwide. Our patient outcomes did not completely reflect the results published by other groups. We herein present the results of 60 patients with hematologic malignancies treated homogeneously on a modified version of the standard protocol by adding ATG as an additional graft-versus-host disease (GVHD) prophylaxis measure. This was a retrospective analysis of 60 haplo-HSCT recipients using a myeloablative conditioning regimen with antithymocyte globulin and PTCy for GVHD prophylaxis. At 5 years, overall survival was 59.2%, relapse-free survival (RFS) was 48.6%, and chronic GVHD (cGVHD) and relapse-free survival was 40%. The median time to neutrophil and platelet engraftment was 16 days and 28.5 days, respectively. The rates of grade II-IV acute GVHD and extensive cGVHD were 46.7% and 23.3%, respectively. The cumulative incidence of relapse was 30%, nonrelapse mortality was 21.6%, and transplantation-related mortality was 11%. Higher Disease Risk Index and 50% HLA match were associated with lower RFS. Female donor to male recipient and older donor age were associated with an elevated risk of cGVHD. The use of PTCy might not yield the same results in different populations. Many remaining questions need to be addressed in randomized trials, including optimal graft source and donor, date of calcineurin inhibitor initiation, personalized or targeted dose of PTCy, immune reconstitution, and others.

Management of adult acute lymphoblastic leukemia in the Gulf Cooperation Council (GCC) countries: A consensus report from the GCC Adult ALL Working Group.

Leukemia burden is growing in the Gulf Council Cooperation (GCC) countries. Nonetheless, there is no unified protocol for managing adult acute lymphoblastic leukemia (ALL) patients in the GCC-countries. Therefore, the GCC Adult-ALL Treaters working group developed this consensus to address the adult-ALL treatment protocols in the GCC-countries and related toxicities' management. Besides, the consensus aimed to highlight the current unmet needs and treatment gaps and provide recommendations to optimize adult-ALL care and patient-centered communication. A three-step modified Delphi method to develop evidence-based recommendations through two-voting rounds and in-between virtual meetings are used in the manuscript development. A 12 experts' panel from five GCC-countries and two international experts were invited to participate in this consensus. This consensus consisted of 35-statements that highlighted the experts' recommendations to optimize ALL adults' care in the first line setting and manage pediatric or pediatric-inspired regimens-related toxicities. Besides, guidance was provided for future research direction and improve patient-centered communication. In conclusion, the adult-ALL management landscape is evolving, and the current evidence highlights better response and survival outcomes with pediatric or pediatric-inspired regiments. Therefore, protocols are needed to optimize the adult-ALL management in the GCC and tailored clinical-trials findings according to the GCC patients' characteristics and local-healthcare infrastructure.

Incidence and risk factors for secondary graft failure in uniformly treated patients with severe aplastic anemia receiving fludarabine and cyclophosphamide for conditioning and matched sibling bone marrow graft as stem cell source.

BACKGROUND AIMS: Graft failure after allogeneic transplant for aplastic anemia is problematic. The risk of graft failure depends on multiple variables, including the preparative regimen, donor type, stem cell dose and source among other variables. METHODS: We performed a retrospective analysis of patients with aplastic anemia who underwent matched-sibling allogeneic transplant at a single center. RESULTS: We identified 82 patients who fit the inclusion criteria. One had primary graft failure and was excluded from this analysis. The recipient median age was 22 years. The donor median age was 23 years. The median time from diagnosis to transplant was 1.6 months. The median number of red cell transfusions before transplant was nine. The median number of platelet transfusions before transplant was 18. Thirteen patients developed secondary graft failure, with a cumulative incidence at 5 years of 16% and median time to develop secondary graft failure of 129 days. All patients engrafted with a median time for neutrophil engraftment of 19 days and a median time for platelet engraftment of 22 days. The survival of patients with or without secondary graft failure was not different. Major or bidirectional ABO incompatibility and older recipient age were statistically significantly associated with greater risk of secondary graft failure. CONCLUSIONS: Secondary graft failure is a significant complication after allogeneic transplant for SAA. Identification of recipients at risk and mitigating the potential risks of this complication is warranted.

Role of Anti-CD38 Monoclonal Antibodies in the Treatment of Adult Immune Hematological Diseases.

Daratumumab is a first-in-class human anti-CD38 IgG1 monoclonal antibody approved for treating newly diagnosed and relapsed refractory multiple myeloma. Pre-clinical data supported daratumumab's ability to deplete autoantibodies producing plasma cells, B-cells, and NK cells. Those reports showed promising results on using daratumumab in autoimmune disorders that are refractory to multiple lines of therapies, which encouraged using daratumumab in various autoimmune conditions that are refractory to standard therapies. This review aims to summarize the literature reporting experience using anti-CD38 antibodies in hematological autoimmune diseases, focusing on the most common autoimmune hematological diseases, including autoimmune hemolytic anemia, immune thrombocytopenia, post-transplant cytopenia, and pure red blood cell aplasia.

Improved survival of adolescents and young adults patients with T-cell acute lymphoblastic leukemia.

Aim: The outcome of T-cell acute lymphoblastic leukemia (T-ALL) has improved with the use of pediatric-inspired protocols in the adolescents and young adults (AYA) population. There is limited literature regarding the outcome of T-ALL/lymphoblastic lymphoma (LBL) AYA patients treated with pediatric protocols. Methods: A total of 35 T-ALL/LBL-AYA patients ages between 14 and 55 years were treated with AYA-15 protocol. Results: At a median follow-up of 5 years the overall survival, disease-free survival and event-free survival are 71%, 62% and 49.6% respectively. Toxicities were within the expected range. Conclusion: Our single-center experience real-world data in treating T-ALL/LBL-AYA patients with pediatric-inspired protocol demonstrates encouraging results of high survival rate and excellent tolerability for patients aged 18-55 years.

"Incidence and significance of donor-specific antibodies in haploidentical stem cell transplantation".

PGF is a devastating complication after allogeneic transplant. We retrospectively analyzed our haploidentical transplant registry to report the incidence and impact of DSA and anti-HLA on engraftment. 107 patients were identified. Median recipient-age of 22, median donor-age of 31. Sixty-two patients had AML (58%), 29 had ALL (27%), 16 (15%) had other malignancies. Sixty-one recipients (57%) had positive anti-HLA, 56 of them had the DSA results available, of these 17 patients had DSAs (15% of the total number of patients, or 28% of patients who have anti-HLA antibodies). The median cumulative MFI was 2062. Sixty-three percent of the DSA were against class-II HLA antigens. The OS, CIR, aGvHD, and cGvHD did not differ between patients with and without anti-HLA antibodies, nor between patients with and without DSA. The gender of the recipient and donor, as well as the gender mismatch between recipient and donor, were statistically associated with the incidence of anti-HLA antibodies. Three patients only developed GF (2.8%), one was primary (0.9%) and the other two secondary GF (1.9%). None of the GF cases was in patients with anti-HLA antibodies or DSA. The presence of anti-HLA or DSAs did not affect the outcomes including the incidence of PGF.

Images in Immunotherapy and Precision Oncology: Angiosarcoma of the Spleen and Liver.

Primary splenic or hepatic angiosarcomas are ultra-rare and aggressive malignancies associated with poor prognosis. The mainstay treatments are surgical resection and chemotherapy. We report a case of angiosarcoma in a 50-year-old woman who presented with bruising, fatigue, ecchymosis, and hepatosplenomegaly. She was treated with the multi-kinase inhibitor sunitinib for 4 weeks before developing a splenic hemorrhage and succumbing. Recent studies have demonstrated the clinical benefit of immunotherapies in angiosarcomas. Additionally, sequencing techniques have showcased the diverse molecular aberrations involved in angiosarcomas, which offer opportunities for precision-matched targeted therapies such as inhibitors of the VEGF/VEGFR axis and PI3K/Akt/mTor pathway.

Recurrence of methotrexate-induced leukoencephalopathy after methotrexate rechallenge: A case report and literature review.

Methotrexate (MTX) is potent chemotherapeutic agent, often administered intrathecally to treat or prevent central nervous system involvement in lymphomas and leukemias, particularly T-cell lymphoblastic leukemia (T-LBL). MTX has been linked to adverse neurologic effects that mimic acute stroke, including facial drooping, hemiplegia, impaired consciousness, and seizures, as well as changes on imaging-known as MTX-induced leukoencephalopathy (LE). We report a case of a 17-year-old male diagnosed with T-LBL, who had been receiving MTX chemotherapy for 4 months. After receiving his fourth dose of MTX, he presented to the emergency department with fever, facial drooping, and acute left-sided weakness. Brain magnetic resonance imaging (MRI) revealed bilateral deep white matter T2 hyperintense foci, increased on the right, with associated diffusion restriction in the right centrum semiovale-consistent with MTX-induced LE. After his symptoms resolved, he was discharged on leucovorin. Six months afterward, he was rechallenged with MTX and developed recurrence of symptoms. Repeat MRI showed well-defined T2/FLAIR hyperintensities in the right centrum semiovale without corresponding diffusion restriction. The left centrum semiovale hyperintensity became less conspicuous in comparison to the previous MRI study. We report a rare case of recurrence of LE after MTX rechallenge and discuss mechanisms, best imaging modalities, and possible treatment options for MTX-induced LE. Given the ominous presentation of MTX-induced LE, we urge clinicians to maintain a high index of suspicion for this condition. Further research is necessary to understand why only certain patients develop recurrence of LE after subsequent doses of MTX.

Treatment of amyloid light chain cardiac amyloidosis: systematic review and future directions.

BACKGROUND: Several treatment strategies for amyloid light chain cardiac amyloidosis (AL-CA) have been described in the literature; however, there is no consensus about the optimal approach to AL-CA. OBJECTIVE: We conducted this systematic review to summarize current evidence from published studies about the safety and efficacy of various treatment regimens for patients with AL-CA, mainly focusing on autologous stem cell transplant (ASCT) and heart transplant. METHODS: An electronic literature search of PubMed, Web of Science, Scopus, EBSCO, and CINAHL Plus was conducted through December 2019 using the relevant keywords and prespecified MeSH terminology. Records were screened, and eligible studies were selected and narratively discussed. Data on the hematologic and cardiac responses as well as the safety of the treatment regimens were extracted and synthesized narratively in the context of the systematic review. RESULTS: Thirty published articles were included in this systematic review. The most commonly used first-line treatment in the included studies was bortezomib-based therapy followed by high-dose melphalan and ASCT, with recent evidence of improved outcome with the addition of daratumumab. Heart transplant was found to extend survival for selected patients who were not eligible for ASCT; however, it was found to affect the patients' tolerance of further chemotherapy in some studies. Published data on longterm outcomes with immunomodulatory agents were scarce. CONCLUSION: Current evidence suggests several possible regimens for the treatment of AL-CA. Effective treatment approaches for AL-CA include induction therapy with bortezomib-based or immunotherapy-based combinations in moderate/severe forms of cardiac involvement, followed by high-dose melphalan and ASCT in eligible patients, and heart transplant for selected severe cases. Therefore, we highlight the necessity of conducting well-designed, randomized controlled trials to provide evidence about the efficacy of these drugs with respect to ASCT.

Allogeneic transplant compared to pediatric-inspired therapy for Philadelphia chromosome-negative adolescent and adult ALL in first complete remission.

BACKGROUND: Pediatric-inspired non-transplant regimens for adolescent and adult ALL patients are becoming standard in many institutions. We aimed to compare a cohort of patients receiving a pediatric-inspired protocol to a cohort of patients treated with adult type ALL therapy followed by allografting after achieving CR1. METHOD: Eighty-five adolescent and adult ALL patients treated with CALGB 19802 protocol who received MSD transplant in CR1 were retrospectively compared to a matched cohort of 72 adolescent and adult ALL patients treated with a modified version of Children's Cancer Group (CCG) 1900 protocol. RESULTS: The five years OS in the allo-HCT cohort was 63.1% compared to 80.2% in the pediatric-inspired chemotherapy arm (P = 0.03). The five years EFS in the allo-HCT arm was 58.8% compared to 61.6% in the pediatric-inspired chemotherapy arm (P = 0.07). The five years DFS in the allo-HCT arm was 58.8% as compared to 71.9% in the pediatric-inspired chemotherapy arm (P = 0.07). The relapse rate in the allo-HCT cohort was 30.58% compared to 21.68% in the pediatric-inspired chemotherapy arm (P = 0.16). The NRM in the allo-HCT cohort was 10.59 as compared to 6.45 in the pediatric-inspired chemotherapy arm (P = 0.3). CONCLUSION: For adolescent and adult patients with Ph-negative ALL, pediatric-inspired chemotherapy resulted in higher OS compared to allo-HCT.

Frontline-matched sibling donor transplant of aplastic anemia patients using primed versus steady-state bone marrow grafts.

Priming donors with G-CSF before BM harvest is reported to improve engraftment and GvHD in recipients. These effects are highly desirable when transplanting patients with non-neoplastic hematologic diseases, particularly AA patients. Here we retrospectively report the outcomes of 39 AA patients receiving a primed BM graft from MSD to 43 patients receiving a steady-state BM graft from MSD, otherwise transplanted using a uniform transplant platform. The graft had higher TNC and CD34 cell concentrations in the primed group (p < 0.001), and that was reflected in higher TNC and CD34 doses per kilogram of recipient in the primed group (p = 0.004 and 0.03, respectively). The OS for primed BM graft recipients was 97.4% and 78.9% for the steady-state BM graft recipients, p-value = 0.01. The cumulative incidence of death without GF was 2.6% in the primed group and 16.3% in the steady-state group, p-value = 0.03. There was no difference in GvHD incidence between the two groups. We confirm that priming improved the TNC and CD34 graft concentration and cell dose; this evidence along with other reported studies constitute reasonable evidence to prove that BM priming improve engraftment. We observed no increase in GvHD using primed BM graft.

Improved survival in adolescents and young adults (AYA) patients aged 14-55 years with acute lymphoblastic leukemia using pediatric-inspired protocol - a retrospective analysis of a real-world experience in 79 of patients treated at a national tertiary care referral center.

BACKGROUND: Treating adolescents and young adults (AYA) patients with acute lymphoblastic leukemia (ALL) using pediatric-inspired protocols have shown improvement in outcomes. Most data available in the literature of such protocols is derived from well-controlled clinical trials. This report aims to provide a real-world experience from using a pediatric-inspired protocol in ALL-AYA population in larger number of patients treated at a national tertiary care referral center. METHODS: Newly diagnosed Philadelphia negative ALL-AYA patients ages between 14 and 55 years of age were treated on an institutional protocol (AYA-15 protocol) adopted from a modified version of Children's Cancer Group (CCG) 1900 protocol. At the time of this publication, a total of 79 patients were treated using the AYA-15 protocol between 2015 and 2020). Event-free survival (FFS), disease-free survival (DFS), and overall survival (OS) were analyzed using cumulative incidence and Kaplan-Meier methods. RESULTS: The median age at diagnosis was 18 years (14-51 years) with 63% male patients. Complete remission (CR) at day 28 of induction was achieved in 88.6% of which 73.4% were minimal residual disease (MRD) negative. At a median follow up of 5 years, EFS, DFS and OS were 57.5%, 69.2% and 75.8% respectively. Toxicities were within the expected range with infections and transaminitis being the most common adverse events. CONCLUSION: Our single-center experience real-world data in treating AYA-ALL patients with pediatric-inspired protocol demonstrates encouraging results of high survival rate and excellent tolerability for patients aged 18-55 years.

Outcomes of autologous stem cell transplantation for multiple myeloma in Saudi Arabia.

BACKGROUND: In 2015, multiple myeloma (MM) represented 1% of all cancers and about 5% of hematologic malignancies in Saudi cancer registry. We conducted this large study because only small pilot studies have examined MM outcomes after autologous stem-cell transplantation (ASCT). The standard therapy for eligible patients is induction chemotherapy followed by ASCT. OBJECTIVES: Determine the demographic characteristics of MM patients and the outcomes of ASCT. DESIGN: Retrospective. SETTING: Tumor registry database of major tertiary cancer care center in Riyadh. PATIENTS AND METHODS: We identified patients with newly diagnosed MM who underwent ASCT from October 1997 to March 2015. MAIN OUTCOME MEASURES: The demographic characteristics of MM patients and the outcomes of ASCT in the form of response evaluation, progression-free survival (PFS) and overall survival (OS). SAMPLE SIZE: 169 patients with newly diagnosed MM. RESULTS: The median age at diagnosis was 51 years (range 23-69) and 100 (59.2%) were male. The most common immunoglobulin (Ig) subtype was IgG-kappa (80 patients; 47.6%). Most patients presented with advanced ISS stage III (75 patients; 47.5%). The cytogenetic analysis was documented in only 87 patients (51.4%); about half (48.3%) had normal cytogenetics by fluorescence in situ hybridization. Deletion 13 was present in 18.4% of patients. In post-induction therapy, 84 patients (50%) achieved a complete response, which increased to 78.1% (132 patients) after ASCT. The median PFS and OS post-transplantation were 30 and 202 months, respectively. Only one patient (<1%) died in the first 100 days after transplantation. CONCLUSIONS: Our transplant eligible MM patients tend to be younger with a higher OS and a low ASCT-related mortality (<1%) than is reported internationally. LIMITATIONS: Usual limitations of a retrospective analysis using registry-level data; no data on quality of life. CONFLICTS OF INTEREST: None.

Full Dose Cyclophosphamide with the Addition of Fludarabine for Matched Sibling Transplants in Severe Aplastic Anemia.

The recommended therapy for severe aplastic anemia (SAA) in younger patients with a matched sibling donor (MSD) is allogeneic hematopoietic cell transplantation (allo-HCT). A number of conditioning regimens and protocols have been used for these patients. Here we report a homogeneous cohort of SAA patients receiving a uniform transplantation protocol. This study is a retrospective analysis of 82 consecutive patients with SAA who underwent MSD allo-HCT at a single center. The median duration of follow-up for survivors was 100 months, the 10-year overall survival (OS) was 87.5%, and the 10-year event-free survival was 75.3%. The OS was 97.4% for "mobilized" bone marrow (BM) graft recipients and 78.9% for "nonmobilized" BM graft recipients (P = .01. The cumulative incidence of acute graft-versus-host disease (GVHD) was 25.6%, that of chronic GVHD was 27.16%, and that of graft failure was 16.2%. Recipient age ≥30 years and transplantation at >6 months after SAA diagnosis were associated with a increased risk of events. In the presence of a fully matched sibling donor, allo-HCT with a mobilized BM graft and fludarabine-cyclophosphamide conditioning is an efficacious and safe approach. Early transplantation is associated with a better outcome, emphasizing the importance of not delaying transplantation in these patients. Prospective trials are needed to determine the optimal regimen.

The outcomes of secondary AML post allogeneic hematopoietic cell transplantation significantly depend on the presence of poor-risk cytogenetic abnormalities.

Secondary acute myeloid leukemia (sAML) includes AML as a complication of an antecedent hematological disorder or a therapy-related AML. Large registry-based data identified sAML as an independent poor-outcome type of AML post allogeneic hematopoietic cell transplantation (allo-HCT). In our study, we tried to define factors affecting outcomes of sAML post allo-HCT, and identify patients with sAML who may truly benefit from allo-HCT. We retrospectively analyzed the data of 64 patients aged (14-61 years) with sAML who received allo-HCT between September 2010 and February 2018 at our institute. Most of the patients were transplanted from matched related donors (MRD; 54, 84.4%). Our results showed that poor-risk cytogenetics were identified in 31 patients (48.4%), and their presence was an indicator of poor overall survival (OS) and disease-free survival (DFS; P-value = .009, and .004, respectively). The cumulative incidence of chronic graft-versus-host disease (cGVHD) was significantly lower in sAML patients with poor-risk cytogenetics (P-value = .003) resulting in a high risk of death without cGVHD in this group of patients (P-value = .02). Besides, GVHD relapse-free survival (GRFS) analysis showed that most of our studied patients experienced either relapse or debilitating grade II-IV cGVHD in the first 2 years post allo-HCT. We conclude that sAML patients with poor-risk cytogenetics have a significantly lower DFS post allo-HCT with a high risk of death without active cGVHD.