Publications by authors named "Samer A Srour"

35 Publications

Bone Marrow versus Peripheral Blood Graft for Haploidentical HCT with Post Transplantation Cyclophosphamide.

Transplant Cell Ther 2021 Sep 16. Epub 2021 Sep 16.

Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX.

Background: In the COVID-19 pandemic era, the numbers of haploidentical hematopoietic cell transplantation (HCT) with peripheral blood (PB) versus bone marrow (BM) grafts increased significantly, which may be associated with adverse outcomes.

Methods: We compared outcomes of BM vs PB grafts in patients ≥18 years with hematological malignancy who underwent T-cell replete haploidentical HCT and graft-versus-host disease (GVHD) prophylaxis with post-transplantation cyclophosphamide, tacrolimus and mycophenolate mofetil.

Findings: Of 264 patients, 180 (68%) received BM and 84 (32%) received PB graft. Median age was 50 years in both groups. Majority (n=199, 75%) received reduced-intensity conditioning. More patients had acute leukemia or myelodysplastic syndrome in BM (n=152, 85%) than PB (n=46, 55%), p<0.01. The median time to neutrophil and platelet engraftment, and incidence of grade II-IV and III-IV acute GVHD (aGVHD) was comparable in both groups. Among grade II-IV aGVHD, steroid-refractory aGVHD (SR-aGVHD) was 9% (95% CI 5-18) in BM vs 32% (95% CI 19-54) in PB; hazard ratio (HR) 3.7, 95% CI 1.5-9.3, p=0.006. Chronic GVHD (cGVHD) was 8% (95% CI 4-13) vs 22% (95% CI 14-36); HR 3.0, 95% CI 1.4-6.6, p=0.005 and systemic therapy-requiring cGVHD was 2.5% (95% CI 1-7) vs 14% (95% CI 7-27), respectively; HR 5.6, 95% CI 1.7-18, p=0.004 at 1 year. PB group had a significantly higher risk of bacterial and viral infections with no appreciable advantage in the duration of hospitalization, immune reconstitution, relapse, non-relapse mortality, or survival.

Interpretation: Our data suggest the use of BM over PB graft for haploidentical HCT.
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http://dx.doi.org/10.1016/j.jtct.2021.09.003DOI Listing
September 2021

Mismatch in SIRPα, a regulatory protein in innate immunity, is associated with chronic GVHD in hematopoietic stem cell transplantation.

Blood Adv 2021 09;5(17):3407-3417

Division of Pathology/Laboratory Medicine, Department of Laboratory Medicine.

Recent compelling evidence showed that innate immune effector cells could recognize allogeneic grafts and prime an adaptive immune response. Signal regulatory protein α (SIRPα) is an immunoglobulin superfamily receptor that is expressed on myeloid cells; the interaction between SIRPα and its ubiquitously expressed ligand CD47 elicits an inhibitory signal that suppresses macrophage phagocytic function. Additional studies showed that donor-recipient mismatch in SIRPα variants might activate monocytic allorecognition, possibly as the result of non-self SIRPα-CD47 interaction. However, the frequency of SIRPα variation and its role in hematopoietic stem cell transplantation (HSCT) remains unexplored. We studied 350 patients with acute myeloid leukemia/myelodysplastic syndrome who underwent HLA-matched related HSCT and found that SIRPα allelic mismatches were present in 39% of transplantation pairs. SIRPα variant mismatch was associated with a significantly higher rate of chronic graft-versus-host disease (GVHD; hazard ratio [HR], 1.5; P = .03), especially de novo chronic GVHD (HR, 2.0; P = .01), after adjusting for other predictors. Those with mismatched SIRPα had a lower relapse rate (HR, 0.6; P = .05) and significantly longer relapse-free survival (RFS; HR, 0.6; P = .04). Notably, the effect of SIRPα variant mismatch on relapse protection was most pronounced early after HSCT and in patients who were not in remission at HSCT (cumulative incidence, 73% vs 54%; HR, 0.5; P = .01). These findings show that SIRPα variant mismatch is associated with HSCT outcomes, possibly owing to innate allorecognition. SIRPα variant matching could provide valuable information for donor selection and risk stratification in HSCT.
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http://dx.doi.org/10.1182/bloodadvances.2021004307DOI Listing
September 2021

Myeloablative Fractionated Busulfan With Fludarabine in Older Patients: Long Term Disease-Specific Outcomes of a Prospective Phase II Clinical Trial.

Transplant Cell Ther 2021 Jul 28. Epub 2021 Jul 28.

Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas. Electronic address:

Compared to reduced-intensity conditioning regimen, myeloablative conditioning (MAC) for hematopoietic stem cell transplantation (HCT) reduces relapse but is avoided in older patients because of higher non-relapse mortality (NRM). To meet the need for a myeloablative regimen for older patients, we developed a novel fludarabine and busulfan MAC regimen. We fractionated the dose of busulfan and gave it for 6 days over a 2-week period and demonstrated the feasibility and safety of this approach. However, the disease-specific efficacy of this regimen is not known. The purpose of this study was to estimate the efficacy of fractionated busulfan regimen by estimating diseases specific survival outcomes. The conditioning regimen consisted of busulfan and fludarabine. On days -13 and -12 before HCT, patients received 80 mg/m busulfan intravenously (IV) daily in an outpatient clinic. Additional chemotherapy was administered during inpatient treatment from day -6 through day -3, including fludarabine 40 mg/m and busulfan IV once daily. The dosing of busulfan was determined from pharmacokinetic analyses to achieve for the course a target area under the curve of 20,000 ± 12% μmol/min, which is close to the average exposure of myeloablative dose of busulfan. One hundred fifty patients with high-risk hematological malignancies up to 75 years were enrolled in this prospective phase II study. The objective was to evaluate NRM, relapse, survival, the rates of graft-versus-host disease (GVHD), and long-term complications. The median age of the patient population was 61 years (interquartile range, 55-67). The most common diagnoses were acute myeloid leukemia (AML; N = 59 [39.3%]), myelodysplastic syndrome (MDS; n = 29 [19.3%]), and myelofibrosis (MF; N = 22 [14.7%]). Most had an unrelated donor (n = 93 [62%]) and received peripheral blood graft (n = 110 [73.3%]). Over half had an HCT-specific comorbidity index of ≥3 (n = 79 [52.7%]). The median follow-up among survivors was 43.4 months (interquartile range, 38.9-50.4). In patients with AML in complete remission, MDS, and myelofibrosis, 3-year overall survival was 66.7% (95% confidence interval [CI], 50.2-88.5%), 43.6% (95% CI, 28.6-66.4%), and 59.1% (95% CI, 41.7-83.7%) respectively. The cumulative incidence of NRM was 22% (15.3%-28.7%), extensive chronic GVHD was 27% (95% CI, 20-34%), bronchiolitis obliterans was 4.7% (95% CI, 1.3-8.1%), and secondary malignancy was 8.7% (95% CI, 4.1-13.2%) at 3 years. Lengthening the duration of busulfan (fractionation) permits safe delivery of myeloablative conditioning in older patients, leading to prolonged survival. © 2021 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.
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http://dx.doi.org/10.1016/j.jtct.2021.07.021DOI Listing
July 2021

Patient-Reported Symptom and Functioning Status during the First 12 Months after Chimeric Antigen Receptor T Cell Therapy for Hematologic Malignancies.

Transplant Cell Ther 2021 Jul 12. Epub 2021 Jul 12.

Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Chimeric antigen receptor (CAR) T cell therapy is being increasingly used to treat patients with advanced hematologic malignancies; however, the symptoms related to standard of care CAR T cell therapy during the first year after treatment have not been assessed using patient-reported outcome (PRO) measurements. This study aimed to quantify patients' perspectives of symptom burden and functional status using PROs during the first year after CAR T cell therapy for hematologic malignancies, especially in patients who experienced grade 2-4 toxicities. Sixty patients were enrolled in this observational cross-sectional study at any time during their first 12 months post-treatment. All 60 had received CAR T cell therapy as standard of care at MD Anderson Cancer Center in 2019. PROs were measured using the MD Anderson Symptom Inventory (MDASI), the PROs Measurement Information System 29 (PROMIS-29), the global health tool EQ5D-5L, and the single-item health-related quality of life scale (HRQoL). Twenty-two additional symptoms related to CAR T cell therapy, as identified by an expert panel, were also evaluated. CAR T cell therapy-related toxicities were rated according to the ASTCT consensus grading criteria. The majority of patients (52 of 60; 87%) received axicabtagene ciloleucel (Yescarta). One-third of the patients developed grade 2-4 cytokine release syndrome or neurotoxicity. The first 90 days after infusion represented the most symptomatic period, in which >10% of patients rated 18 symptoms as severe (ie, MDASI symptom score of 7 to 10 on scale of 0 to 10), strongly indicating the need for effective symptom management. Physical functioning, measured by interference on the "general activity" item on the MDASI and this domain on the PROMIS-29, were significantly worse in patients who underwent therapy during the first 30 days compared with those who underwent therapy over 90 days (all P < .05 with the Hochberg step-up procedure), whereas the EQ5D-5L and single-item HRQoL did not detect such differences. Compared with patients who had mild cytokine release syndrome or neurotoxicity (grade 0-1), patients who developed grade 2-4 toxicities persistently reported multiple severe symptoms after 30 days following therapy (all P < .05). Furthermore, although using a different recall period, patient-reported scores on several PROMIS-29 domains were significantly correlated with the scores of corresponding MDASI symptom items. This real-world quantitative PRO symptoms study provides evidence of unique profiles of the physical, psychological, and cognitive symptom burden in patients undergoing CAR T cell therapy that varies within the first year after infusion and demonstrates differences among PRO measurement scales. These results support the need for validation of fit-for-purpose PRO measurements for routinely monitoring symptom and toxicity burdens in CAR T cell therapy care settings.
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http://dx.doi.org/10.1016/j.jtct.2021.07.007DOI Listing
July 2021

CRP and ferritin in addition to the EASIX score predict CAR-T-related toxicity.

Blood Adv 2021 07;5(14):2799-2806

Department of Stem Cell Transplantation and Cellular Therapy.

The Endothelial Activation and Stress Index (EASIX) score, defined as [(creatinine × lactate dehydrogenase [LDH])/platelets], is a marker of endothelial activation that has been validated in the allogeneic hematopoietic stem cell transplant setting. Endothelial activation is one of the mechanisms driving immune-mediated toxicities in patients treated with chimeric antigen receptor-T (CAR-T)-cell therapy. This study's objective was to evaluate the association between EASIX and other laboratory parameters collected before lymphodepletion and the subsequent onset of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) those patients. Toxicity data were collected prospectively on 171 patients treated with axicabtagene ciloleucel (axi-cel) for large B-cell lymphoma (LBCL). CRS grades 2 to 4 were diagnosed in 81 (47%) patients and ICANS grades 2 to 4 in 84 (49%). EASIX combined with ferritin (EASIX-F) identified 3 risk groups with CRS grades 2 to 4 cumulative incidence of 74% (hazards ratio [HR], 4.8; 95% confidence interval [CI], 2.1-11; P < .001), 49% (HR, 2.3; 95% CI, 1.02-5; P = .04), and 23% (reference), respectively. EASIX combined with CRP and ferritin (EASIX-FC) identified 3 risk groups with an ICANS grade 2 to 4 cumulative incidence of 74% (HR, 3.6; 95% CI, 1.9-6.9; P < .001), 51% (HR, 2.1; 95% CI, 1.1-3.9; P = .025), and 29% (reference). Our results indicate that common laboratory parameters before lymphodepletion correlate with CAR-T-related toxicities and can help support clinical decisions, such as preemptive toxicity management, hospitalization length, and proper setting for CAR-T administration.
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http://dx.doi.org/10.1182/bloodadvances.2021004575DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8341350PMC
July 2021

Patient-Reported Outcomes for Cancer Patients with Hematological Malignancies Undergoing Chimeric Antigen Receptor T Cell Therapy: A Systematic Review.

Transplant Cell Ther 2021 05 7;27(5):390.e1-390.e7. Epub 2021 Jan 7.

Department of Symptom Research, The University of Texas MD Anderson Cancer Center, Houston, Texas. Electronic address:

Databases were searched to identify studies published over the past 10 years that addressed the utility of patient-reported outcomes (PROs) in patients receiving chimeric antigen receptor (CAR) T cell therapy in patients with hematological malignancies. Among 280 records, three articles covering 206 patients were eligible. The data were prospectively collected at multiple time points. The compliance rates were 70% to 94%. There was an inverse relationship between fatigue and social function among adults. The quality of life (QoL) improvement and ability to complete PROs were linked to disease status. About 40% of adults reported at least some cognitive difficulties, with a detrimental impact on mental and physical health status. In adults, the most commonly reported cognitive impairment was memory difficulties. Depression was associated with cognitive difficulties. Younger adults were at higher risk of long-term poor mental health, anxiety, and depression. For pediatric and adolescent patients, emotional dysfunction improves over time. QoL status improved over time; yet, severe cytokine release syndrome and neurotoxicity caused delayed improvement. Information regarding whether the PROs were integrated into medical records and clinical guidelines is lacking. Utilizing PROs in patients on CAR T cell therapy seems feasible and informative. Studies utilizing larger sample sizes and using validated PRO tools at different time points remain unmet needs.
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http://dx.doi.org/10.1016/j.jtct.2021.01.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8110951PMC
May 2021

Acute graft-versus-host disease is the foremost cause of late nonrelapse mortality.

Bone Marrow Transplant 2021 Aug 12;56(8):2005-2012. Epub 2021 Apr 12.

Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Despite low nonrelapse mortality (NRM) at day 100 after allogeneic hematopoietic cell transplantation (HCT), NRM at 1 year remains substantial. In this study, we retrospectively analyzed 199 patients who were treated on a phase II clinical trial assessing safety and efficacy of myeloablative fractionated busulfan and fludarabine conditioning regimen for hematologic malignancies. The goal of the study was to identify factors associated with NRM occurring between days 101 and 365 post-HCT and generate a hypothesis for future studies to reduce the risk of NRM at 1 year. We found that a vast majority (83%) of patients who experienced NRM between days 101 and 365 had prior grade II-IV acute graft-versus-host disease (GVHD), which was the leading cause of death either by itself (33.3%) or complicated by infections (37.5%). In multivariate analysis, grade II-IV acute GVHD (hazard ratio (HR) 2.9, 95% confidence interval (CI) 1.3-6.6, p = 0.01) was the only significant predictor of NRM between days 101 and 365. Measures to reduce the risk of acute GVHD could lower the risk of NRM at 1 year and improve overall survival.
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http://dx.doi.org/10.1038/s41409-021-01274-1DOI Listing
August 2021

Influence of Overlapping Genetic Abnormalities on Treatment Outcomes of Multiple Myeloma.

Transplant Cell Ther 2021 03 20;27(3):243.e1-243.e6. Epub 2020 Dec 20.

Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Numerous genetic abnormalities affect treatment outcomes in multiple myeloma. The role of coexistent trisomy or hyperdiploidy and high-risk cytogenetic abnormalities (CGAs) is not well defined. We assessed the influence of overlapping genetic abnormalities in patients who received frontline autologous stem cell transplantation. A total of 491 consecutive patients between January 2009 and January 2016 were identified. High-risk CGAs included del(17p), t(4;14), t(14;16), and gain 1q21 by fluorescence in situ hybridization and del(13) by conventional cytogenetics. Thirty-two percent had a trisomy, 27% had a high-risk CGA, and 11% had both. Among patients with any trisomy, 3-year progression-free survival (PFS) and overall survival (OS) were 60% and 90%, respectively, compared to 25% and 65%, respectively, for patients with any high-risk CGA. Patients with co-existent trisomy and high-risk CGAs had 3-year PFS and OS of 43% and 89%, respectively, whereas those with isolated high-risk CGAs without trisomy had 3-year PFS and OS of 13% and 49%, respectively. The PFS (hazard ratio [HR], 1.9; 95% confidence interval [CI], 1.1 to 3.3; P = .02) and OS (HR, 4.5; 95% CI, 1.5 to 13; P = .006) were worse for high-risk CGAs without versus those with concurrent trisomies. Our findings suggest a protective impact of trisomies in patients with high-risk CGAs and a potential need for revised risk stratification assessments to account for overlapping genetic abnormalities.
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http://dx.doi.org/10.1016/j.jtct.2020.10.021DOI Listing
March 2021

Impact of Mixed Chimerism on Myelofibrosis Outcomes after Allogeneic Hematopoietic Stem Cell Transplantation.

Biol Blood Marrow Transplant 2020 12 17;26(12):e301-e302. Epub 2020 Sep 17.

Department of Stem Cell Transplantation & Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas.

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http://dx.doi.org/10.1016/j.bbmt.2020.09.003DOI Listing
December 2020

Chimeric Antigen Receptor Therapy: How Are We Driving in Solid Tumors?

Biol Blood Marrow Transplant 2020 10 2;26(10):1759-1769. Epub 2020 Jul 2.

Department of Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, Texas. Electronic address:

Immune effector cell (IEC) therapy is emerging as a promising approach in the field of cancer immunotherapy. Clinical IEC trials, predominantly using chimeric antigen receptor (CAR) T cells, have shown excellent responses in CD19 B cell malignancies and multiple myeloma. In solid tumors, preclinical data are encouraging, but clinical data are in their infancy, and there are challenges in using CAR T therapy in this setting, including (1) on-target off-tumor toxicity, (2) optimal target identification, (3) effective trafficking into bulky tumor tissue, and (4) resistance to tumor immune evasion mechanisms. Novel techniques and modifications are being explored in both the preclinical and clinical settings, aiming to improve treatment efficacy and address the aforementioned obstacles to successful CAR T therapy in solid tumors. Here we review these challenges in a clinically oriented approach and summarize published clinical trials using CAR T therapy in a variety of solid tumors.
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http://dx.doi.org/10.1016/j.bbmt.2020.06.020DOI Listing
October 2020

Haploidentical transplants for patients with relapse after the first allograft.

Am J Hematol 2020 Jul 3. Epub 2020 Jul 3.

Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Relapse after allogeneic hematopoietic stem-cell transplantation (AHSCT) is associated with very poor outcomes. A second transplant offers the possibility of long-term disease control. We analyzed outcomes with haploidentical donors for second allograft at our institution. All consecutive patients with hematological malignancies (N = 29) who relapsed after AHSCT and underwent a haploidentical transplant (haploSCT) as second transplant between February 2009 and October 2018 were included. Median age was 36 years (interquartile range (IQR) 24-60); 83% of patients had high/very high disease risk index; 61% of AML/MDS patients had high-risk cytogenetics; and only 24% were in complete remission at transplant. With a median follow-up of 46.9 months, the 3-year relapse, non-relapse mortality (NRM), progression-free survival (PFS) and overall survival (OS) were 30%, 39%, 31% and 40%, respectively. In multivariable analysis (MVA), comorbidity index (HCT-CI) and detectable donor-specific anti-HLA antibodies (DSA) prior to second transplant were significantly associated with worse outcomes. Patients with HCT-CI <3 and without DSA had 3-year PFS and OS of 53% and 60.3%, respectively. Our findings suggest that haploSCT as second AHSCT is feasible and potentially curative. Lower HCT-CI and no DSA were associated with lower NRM and improved survival. Haploidentical grafts might be a preferred donor source for second AHSCT as these are high-risk patients who frequently need to proceed urgently to transplant.
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http://dx.doi.org/10.1002/ajh.25924DOI Listing
July 2020

Cytogenetics and Blast Count Determine Transplant Outcomes in Patients with Active Acute Myeloid Leukemia.

Acta Haematol 2021 30;144(1):74-81. Epub 2020 Jun 30.

Department of Stem Cell Transplantation, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Acute myeloid leukemia (AML) patients not in remission and beyond first or second complete remission are considered allogeneic stem cell transplant (SCT) candidates. We present 361 patients who underwent SCT from matched related or unrelated donors between 2005 and 2013. The purpose was to identify a subgroup of patients with active disease at the time of transplant that benefit. Cox proportional hazards regression analysis was used for univariate and multivariate analyses to predict overall survival (OS). Variables considered were age, sex, SWOG cytogenetic risk group, bone marrow (BM) and peripheral blood (PB) blast percentage, regimen intensity, and type of AML. At a median of 26 months after transplantation, OS, progression-free survival (PFS), non-relapse mortality, and relapse rates were 26, 24, 23, and 48%, respectively. In a univariate analysis, risk cytogenetics (p < 0.001) and BM blasts >4% (p = 0.006) or any blasts in PB (p < 0.001) indicated worse OS. In a multivariate analysis, patients with <5% BM blasts or absence of circulating blasts and good or intermediate risk cytogenetics had significantly superior OS (46%), PFS (44%), and disease progression at 3 years. Based on these findings, patients not in remission with good or intermediate risk cytogenetics and low blast counts should be considered for SCT.
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http://dx.doi.org/10.1159/000507012DOI Listing
March 2021

Haploidentical transplants for patients with graft failure after the first allograft.

Am J Hematol 2020 Jun 29. Epub 2020 Jun 29.

Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas.

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http://dx.doi.org/10.1002/ajh.25917DOI Listing
June 2020

Chimeric antigen receptor T-cell therapy toxicities.

Br J Clin Pharmacol 2021 06 7;87(6):2414-2424. Epub 2020 Aug 7.

Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Cancer immunotherapy has greatly advanced in recent years, with chimeric antigen receptor (CAR) T cells emerging as an innovative technology that harnesses the immune system to fight malignant diseases. These genetically engineered T-cells have shown encouraging results for B-cell lymphoid malignancies and are now being explored for other cancer types. However, this novel adoptive cell therapy is associated with a new spectrum of immune-mediated adverse events and toxicities. As CAR T cells recognize and engage tumour cells, cytokines are secreted and activate other immune cells, frequently leading to rapid development of cytokine release syndrome, which can result in acute deterioration of the patient's clinical condition. In many patients, cytokine release syndrome is mild and easy to manage, but others experience persistent fevers accompanied by hypotension and hypoxia, which require management with immune-modulatory agents. Another deleterious effect of cytokines released by effector cells is immune effector cell-associated neurotoxicity syndrome. This syndrome, caused by a disruption of the blood-brain barrier as a consequence of the immune process, can result in rapid deterioration in cognitive function. This is often associated with subtle changes in handwriting, often progressing to loss of memory and concentration and reduced ability to name objects or follow commands. In some cases, the neurological state is further compromised by seizures and in rare instances with fulminant life-threatening cerebral oedema. In this review, we discuss these toxicities, as well as other CAR T-cell-related immune phenomenon, and address their clinical manifestations, grading, and management options.
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http://dx.doi.org/10.1111/bcp.14403DOI Listing
June 2021

Impact of renal impairment on light chain amyloidosis outcomes after autologous hematopoietic stem cell transplantation.

Ann Transl Med 2020 Apr;8(7):509

Department of Stem Cell Transplantation & Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

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http://dx.doi.org/10.21037/atm.2020.01.27DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7210159PMC
April 2020

Idiopathic refractory ascites after allogeneic stem cell transplantation: a previously unrecognized entity.

Blood Adv 2020 04;4(7):1296-1306

Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX.

At our center, we observed a series of patients who developed transudative refractory ascites secondary to noncirrhotic, non-veno-occlusive disease (VOD)-related portal hypertension after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Patients were considered to have idiopathic portal hypertension-related refractory ascites (IRA) if they developed ascites secondary to intrahepatic portal hypertension (serum ascites albumin gradient ≥1.1 g/dL or hepatic venous pressure gradient [HVPG] >5 mm Hg), but did not meet the clinical criteria for classical VOD/sinusoidal obstructive syndrome (SOS) and did not have any alternate etiology of portal hypertension. From our institutional database, we identified 40 patients who developed IRA after allo-HSCT between 2004 and 2018. The patients' median age at the time of allo-HSCT was 54 years (range, 21-73 years). The median time to development of IRA after allo-HSCT was 80 days (range, 16-576 days). The median number of paracentesis was 3 (range, 1-11), and 15 (38%) patients had an intraperitoneal catheter placed for continued drainage of the rapidly accumulating ascites. Portal pressures were measured in 19 patients; 6 (15%) had moderate portal hypertension (HVPG 6-9 mm Hg), and 13 (33%) had severe portal hypertension (HVPG ≥ 10 mm Hg). Liver biopsy was performed in 24 patients. None of the patients met the criteria for classical VOD/SOS (clinical/histological) or cirrhosis (histological). The cumulative incidence of nonrelapse mortality was 63%, and the median survival duration after the development of the IRA was 7 months (range, 0.8-125.6 months). IRA is a poorly understood and often fatal complication of allo-HSCT.
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http://dx.doi.org/10.1182/bloodadvances.2019000638DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7160275PMC
April 2020

Endothelial Activation and Stress Index (EASIX) at Admission Predicts Fluid Overload in Recipients of Allogeneic Stem Cell Transplantation.

Biol Blood Marrow Transplant 2020 05 9;26(5):1013-1020. Epub 2020 Feb 9.

Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas. Electronic address:

Fluid overload (FO) grade ≥2 (more than 10% weight gain from baseline) has recently been recognized as an important toxicity associated with a high rate of nonrelapse mortality in recipients of allogeneic hematopoietic cell transplantation (AHCT). The causes for FO remain unclear. We hypothesized that endothelial damage, possibly due to treatments received prior to AHCT, may be associated with this toxicity and sought to determine whether the Endothelial Activation and Stress Index (EASIX) (defined as lactate dehydrogenase [U/L] × creatinine [mg/dL]/platelets [10 cells/L]) correlates with grade ≥2 FO in 2 cohorts of recipients of AHCT at our institution. We tested our hypothesis in a cohort of 145 consecutive recipients (study cohort) of AHCT transplant from HLA-haploidentical donors and validated the findings in a cohort of 449 (validation cohort) recipients of AHCT from HLA-matched donors who underwent transplantation between 2010 and 2015. Predictors of grade ≥2 FO were evaluated using competing risks regression in univariate analysis and classification and regression tree (CART) analysis in multivariate analysis. The cumulative incidence of grade ≥2 FO was estimated considering death as a competing risk. EASIX scores were evaluated based on log-transformed values. Optimal predictive EASIX cutoff values were determined based on receiver operating characteristics curve analysis. Grade ≥2 FO occurred in 21% and 6% of the study and validation cohorts, respectively, with the majority of these cases being diagnosed before the day of AHCT. Median log EASIX score at admission was 2.4 (interquartile range [IQR], 1.3, 3.7) and 2.5 (IQR, 1.4, 3.9) in the 2 respective cohorts. In univariate analysis, high EASIX at admission was a significant predictor of grade ≥2 FO in the study (cutoff: 4.4, hazard ratio [HR] = 4.8, P < .001) and in the validation (cutoff: 4.3, HR = 4.8, P < .001) cohorts. The significant effect of EASIX persisted in multivariate CART analysis in the study (HR = 6.3, P < .001) and the validation (HR = 28, P = .002) cohorts. Additional predictors in multivariate analysis included body weight below 80 kg in recipients older than 55 years (HR = 4.5, P < .001) in the study cohort and diabetes (HR = 34, P = .001) and age >60 years (HR = 9.6, P = .04) in the validation cohort. At admission, the prevalence of EASIX score of >4.3 (18% versus 17%, P = .9) was not different between the diabetics and nondiabetics. EASIX score at admission is a significant predictor of grade ≥2 FO in recipients of AHCT from HLA-haploidentical or HLA-matched donors. Independently of EASIX, older patients with low weight were associated with increased risk of grade ≥2 FO for recipients of HLA-haploidentical transplants. For the HLA-matched cohort, diabetes and older age were associated with increased FO risk. These findings require validation in external cohorts.
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http://dx.doi.org/10.1016/j.bbmt.2020.01.028DOI Listing
May 2020

Haploidentical transplantation for acute myeloid leukemia patients with minimal/measurable residual disease at transplantation.

Am J Hematol 2019 12 21;94(12):1382-1387. Epub 2019 Oct 21.

Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas.

There have been conflicting results regarding the impact of minimal/measurable disease at transplant on acute myeloid leukemia (AML) outcomes after haploidentical transplantation (haplo-SCT). We assessed the impact of pre-transplant disease status on post-transplant outcomes of 143 patients treated with haplo-SCT using fludarabine-melphalan (FM) conditioning and post-transplant cyclophosphamide (PTCy). With a median follow-up of 29 months, the two-year PFS for all patients was 41%. Compared to patients in complete remission (CR) at transplant, those with active disease (n = 29) and CR with incomplete count recovery (CRi) (n = 39) had worse PFS. They had hazard ratios (HR) of 3.5 (95% CI: 2.05-6.1; P < .001) and 2.3 (95% CI: 1.3-3.9; P = .002), respectively. Among patients who were in CR at transplant, there were no differences in PFS between those who had minimal residual disease (MRD) positive (n = 24), and MRD negative (n = 41) (HR 1.85, 95%CI: 0.9-4.0; P = .1). In multivariable analysis for patients in CR, only age was predictive for outcomes, while MRD status at transplant did not influence the treatment outcomes. Our findings suggest that haplo-SCT with FM conditioning regimen and PTCy-based GVHD prophylaxis has a protective effect, and may potentially abrogate the inferior outcomes of MRD positivity for patients with AML. Patients with positive MRD may benefit from proceeding urgently to a haplo-SCT, as this does not appear to negatively impact transplant outcomes.
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http://dx.doi.org/10.1002/ajh.25647DOI Listing
December 2019

Haploidentical vs haplo-cord transplant in adults under 60 years receiving fludarabine and melphalan conditioning.

Blood Adv 2019 06;3(12):1858-1867

Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX.

Haplo-identical transplant with posttransplant cyclophosphamide (haplo) and umbilical cord blood transplant supported by third-party CD34 cells (haplo-cord) are competing approaches to alternative donor transplant. We compared, in adults younger than age 60 years, the outcomes of 170 haplo at 1 institution with that of 137 haplo-cord at 2 other institutions. All received reduced intensity conditioning with fludarabine and melphalan ± total body irradiation. GVHD prophylaxis for haplo consisted of cyclophosphamide, tacrolimus, and mycophenolate, whereas haplo-cord received antithymocyte globulin, tacrolimus, and mycophenolate. Haplo transplant used mostly bone marrow, and peripheral blood stem cells were used in haplo-cord transplants. Haplo-cord were older and had more advanced disease. Haplo-cord hastened median time to neutrophil (11 vs 18 days, = .001) and platelet recovery (22 vs 25 days, = .03). At 4 years, overall survival (OS) was 50% for haplo-cord vs 49% for haplo. Progression-free survival (PFS) was 40% for haplo-cord vs 45% for haplo. In multivariate analysis, the disease risk index was significant for OS (hazard ratio, 1.8; 95% confidence interval, 1.48-2.17; = .00) and PFS. Total body irradiation was associated with decreased recurrence and improved PFS, age >40 with increased nonrelapse mortality. The type of transplant had no effect on OS, PFS, relapse, or nonrelapse mortality. Cumulative incidence of grade 2-4 acute graft-versus-host disease (GVHD) by day 100 was 16% after haplo-cord vs 33% after haplo ( < .0001), but grade 3-4 GVHD was similar. Chronic GVHD at 1 year was 4% after haplo-cord vs 16% after haplo ( < .0001). Haplo or haplo-cord results in similar and encouraging outcomes. Haplo-cord is associated with more rapid neutrophil and platelet recovery and lower acute and chronic GVHD. Institutional review board authorization for this retrospective study was obtained at each institution. Some patients participated in trials registered at www.clinicaltrials.gov as #NCT01810588 and NCT01050946.
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http://dx.doi.org/10.1182/bloodadvances.2019000200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6595267PMC
June 2019

Comparison of Outcomes of Allogeneic Hematopoietic Cell Transplantation for Multiple Myeloma Using Three Different Conditioning Regimens.

Biol Blood Marrow Transplant 2019 05 11;25(5):1039-1044. Epub 2019 Jan 11.

Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas. Electronic address:

Allogeneic hematopoietic cell transplantation (allo-HCT) is a potentially curative therapy for patients with multiple myeloma, as it provides a graft-versus-myeloma effect alongside a myeloma-free graft. Although reduced-intensity conditioning regimens decrease nonrelapse mortality (NRM), there is a paucity of data with regard to the ideal conditioning regimen in myeloma. We conducted a retrospective comparison of 3 different preparative regimens used for allo-HCT for multiple myeloma at our institution in recent clinical trials: busulfan/fludarabine (BuFlu), fludarabine/melphalan 100 mg/m (FM100), and fludarabine/melphalan 140 mg/m (FM140). NRM, progression-free survival (PFS) at 3 years, and overall survival (OS) at 3 years were the primary endpoints. Secondary endpoints included time to engraftment, and the incidence of grades II through IV acute graft-versus-host disease and chronic graft-versus-host disease. A total of 73 patients received allo-HCT with these regimens. NRM at 3 years was seen in 3 (21%), 5 (28%), and 6 (24%) patients in the BuFlu, FM100, and FM140 groups, respectively. Three-year PFS in the BuFlu, FM100, and FM140 groups was 16% (hazard ratio [HR], 1.2; 95% confidence interval [CI], 0.6 to 2.1), 26% (HR, 0.6; 95% CI, 0.3 to 1.2), and 11% (reference), respectively. Three-year OS in the BuFlu, FM100, and FM140 groups was 39% (HR, 1.1; 95% CI, 0.5 to 2.2), 43% (HR, 0.7; 95% CI, 0.3 to 1.4), and 32% (reference), respectively. High-risk cytogenetics and relapsed disease prior to allo-HCT were found to be independent predictors of inferior OS on multivariate analysis, with a HR of 2.1 (P = .02) and 2.6 (P = .004), respectively. In contrast, the preparative regimen did not emerge as a predictor of PFS or OS. Durable clinical remission can be achieved in 11% to 25% of patients with multiple myeloma with the use of allo-HCT without any significant difference in the safety or efficacy of the conditioning regimen. High-risk cytogenetics and relapsed disease prior to transplant were associated with inferior PFS and OS.
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http://dx.doi.org/10.1016/j.bbmt.2019.01.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7053532PMC
May 2019

Fludarabine with a higher versus lower dose of myeloablative timed-sequential busulfan in older patients and patients with comorbidities: an open-label, non-stratified, randomised phase 2 trial.

Lancet Haematol 2018 Nov;5(11):e532-e542

Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Background: Haemopoietic stem-cell transplantation (HCT) conditioning regimens that can reduce risk of relapse without increasing non-relapse mortality are needed. We aimed to test the safety of timed-sequential delivery of low-dose versus high-dose myeloablative busulfan in older patients and patients with comorbidities.

Methods: This non-stratified, open-label, randomised phase 2 trial was done at The University of Texas MD Anderson Cancer Center (Houston, TX, USA). Patients with haematological cancers aged between 5 and 75 years were eligible to participate in the study. Patients who had HIV or uncontrollable infections were excluded. Eligible patients were randomly assigned (1:1 by a computer-generated programme in block sizes of four) to receive a total intravenous busulfan dose to achieve an area under the curve of 16 000 μmol/min (16K group) or 20 000 μmol/min (20K group) on the basis of pharmacokinetic analysis, plus intravenous fludarabine 40 mg/m for 4 days. The investigators and the research nurses were masked to the block size to conceal allocation. The primary outcome was day 100 non-relapse mortality. All analyses were by modified intention to treat, including only patients who received at least one dose of the study drug. No interim analyses were planned and accrual is complete. This study is registered with ClinicalTrials.gov, number NCT01572662.

Findings: Between April 18, 2012, and Dec 9, 2015, 98 patients were enrolled. 49 patients were randomly assigned to the 16K group and 49 to the 20K group, one of which was removed from the study before starting the intervention. Median age was 60 years (IQR 54-67). 50 (52%) patients had an HCT-specific comorbidity index score of 3 or more, and 41 (42%) had a high or very high Disease Risk Index score. Day 100 non-relapse mortality was 4% (95% CI 0-10) in the 16K group and 6% (0-13) in the 20K group (p=0·65). Infection was the most common grade 3-5 toxicity in both the 20K group (25 [52%] of 48 patients) and the 16K group (24 [49%] of 49 participants). Mucositis (nine [19%] of 48 patients vs three [6%] of 49 patients), idiopathic pneumonia syndrome (nine [19%] of 48 patients vs two [4%] of 49 patients), and culture-negative neutropenic fever (16 [33%] of 48 patients vs eight [16%] of 49 patients) were more common in the 20K group than in the 16K group.

Interpretation: Myeloablative doses of busulfan administered in a timed-sequential manner with fludarabine is associated with low non-relapse mortality in older patients and patients with comorbidities. Additional studies are required to show whether this approach can reduce the risk of relapse.

Funding: Cancer Center Support Grant (US National Cancer Institute, National Institutes of Health).
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http://dx.doi.org/10.1016/S2352-3026(18)30156-XDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6317874PMC
November 2018

Four-year follow-up of a single arm, phase II clinical trial of ibrutinib with rituximab (IR) in patients with relapsed/refractory mantle cell lymphoma (MCL).

Br J Haematol 2018 08 22;182(3):404-411. Epub 2018 May 22.

Department of Lymphoma and myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Ibrutinib has shown significant activity in patients with relapsed or refractory mantle cell lymphoma (RR-MCL). We report the long-term outcome and safety profile of a single-centre, single arm, open-label, phase 2 study of RR-MCL treated with IR. Overall, the median follow-up time was 47 months (range 1-52 months), median duration on treatment was 16 months (range 1-53 months) and median number of treatment cycles was 17 (range 1-56). Twenty-nine patients (58%) achieved complete remission and of these, 12 patients continue on study. Thirty-eight patients discontinued treatment, 14 due to disease progression (2 transformed). Patients with blastoid morphology, high risk MCL International Prognostic Index score and high Ki67% had inferior survival. The commonest grade 1-2 toxicities were fatigue, diarrhoea, nausea, arthralgias and myalgias. None had long term toxicities. Median progression-free survival was 43 months. Eighteen patients (36%) died (14 deaths were MCL-related). The median overall survival has not been reached. Treatment with IR can provide durable remissions in a subset of patients with RR-MCL, especially those with low Ki67%. The possible benefit of adding other therapies in combination with IR in RR-MCL is under exploration.
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http://dx.doi.org/10.1111/bjh.15411DOI Listing
August 2018

Paraneoplastic Hyperleukocytosis in Pancreatic Adenocarcinoma.

J Pancreat Cancer 2017 1;3(1):84-86. Epub 2017 Nov 1.

Division of Hematology and Oncology, Baylor College of Medicine, Houston, Texas.

Paraneoplastic hyperleukocytosis is a rare phenomenon observed in patients with adenocarcinomas and other malignancies. In this study, we present a case of paraneoplastic hyperleukocytosis in pancreatic adenocarcinoma secondary to excessive secretion of serum granulocyte colony-stimulating factor (G-CSF). We report a 71-year-old Caucasian male who presented to our hospital with hyperleukocytosis in the setting of locally advanced pancreatic adenocarcinoma. The patient was recently diagnosed 4 months before presentation and received abraxane/gemcitabine in addition to palliative radiation therapy for continued gastrointestinal bleeding. During routine laboratory assessment, the patient was found to have a white blood cell (WBC) count of 153 K/UL (75% neutrophils and 14% bands). Bone marrow biopsy and cytology were negative for neoplastic features. Serum G-CSF levels returned markedly elevated, supporting the diagnosis of paraneoplastic hyperleukocytosis. Interestingly, the WBC count decreased significantly following each of two cycles of chemotherapy, further suggesting a paraneoplastic etiology of hyperleukocytosis. The patient did not receive any growth factor support at any point before or during treatment. In conclusion, the presence of hyperleukocytosis in cancer should raise clinical suspicion of a paraneoplastic phenomenon when other possible causes have been excluded. Hyperleukocytosis in this setting may correlate with progression of disease and lessen with treatment.
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http://dx.doi.org/10.1089/pancan.2017.0019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5933489PMC
November 2017

Impact of Health Care Insurance Status on Treatment Outcomes of Acute Myeloid Leukemia.

Clin Lymphoma Myeloma Leuk 2017 07 10;17(7):450-456.e2. Epub 2017 May 10.

Departement of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK.

Introduction: Insurance status has been found to influence treatment outcomes in various solid tumors. Limited data with conflicting results are available in patients with acute myeloid leukemia (AML). We examined the impact of health insurance at diagnosis on AML treatment outcomes.

Patients And Methods: All consecutive adult patients (≥ 18 years of age) diagnosed with AML between 2002 and 2011 and followed through August 2013 were included. Survival estimates were calculated by Kaplan-Meier survival curves. Logistic regression and multivariate Cox proportional hazards methods were used to explore the influence of multiple baseline covariates on treatment outcomes.

Results: A total of 217 patients with complete medical records were identified. Of these, 161 patients had complete cytogenetic/molecular data for risk stratification and were included in the final efficacy analyses. Most patients (45.8%) were publicly insured, 36.3% were privately insured, and 17.3% were uninsured. No significant association was found between insurance source and cytogenetic/molecular risk status. Transplantation information was available for 157 patients, with no significant association found between transplant receipt and insurance source. After adjustment for age, cytogenetic/molecular risk, and transplant receipt, we found no statistically significant association between the insurance source and either event-free or overall survival.

Conclusion: Insurance source at diagnosis has no impact on AML treatment outcomes. The consistency of our results with some, but not all, studies is probably driven primarily by access-to-care eligibility requirements among different states. Further efforts to better understand such disparities are warranted.
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http://dx.doi.org/10.1016/j.clml.2017.05.011DOI Listing
July 2017

A randomized phase II study of standard-dose versus high-dose rituximab with BEAM in autologous stem cell transplantation for relapsed aggressive B-cell non-hodgkin lymphomas: long term results.

Br J Haematol 2017 08 9;178(4):561-570. Epub 2017 May 9.

Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer, Houston, TX, USA.

High-dose rituximab (HD-R) combined with carmustine, cytarabine, etoposide and melphalan (BEAM) and autologous stem cell transplant (ASCT) was effective and tolerable in a single-arm prospective study of relapsed aggressive B-cell non-Hodgkin lymphoma (R-NHL). We performed a randomized phase 2 study comparing HD-R versus standard-dose rituximab (SD-R) in R-NHL. Ninety-three patients were randomized to HD-R (1000 mg/m ) (n = 42) or SD-R (375 mg/m ) (n = 51) administered on post-transplant days +1 and +8, using a Bayesian adaptive algorithm. The 2 treatment arms were balanced in regards to patient demographic and clinical characteristics. At a median follow-up of 7·92 years, the 5-year disease-free survival (DFS) and overall survival (OS) were 40% and 48%, respectively. We found no statistically significant differences between HD-R and SD-R in 5-year DFS (36% vs. 43%; P = 0·205) and OS (43% vs. 52%; P = 0·392). In multivariate analyses, only disease status before ASCT [residual disease versus complete remission (CR)] (hazard ratio [HR] 1·79, 95% confidence interval [CI]: 1·08-2·95) and number of prior treatments received (>2 vs. ≤2 lines of treatment) (HR 1·89, 95% CI: 1·13-3·18) were associated with worse DFS and OS. Patients who had SCT while in CR or who received ≤2 lines of treatment prior to SCT had better 5-year OS (57% vs. 35%; P = 0·02 and 54% vs. 30%, P = 0·001, respectively) in both arms. No differences in engraftments or adverse events were noted in the 2 arms. When combined with BEAM and ASCT in relapsed aggressive B-cell NHL, HD-R provided no DFS or OS advantage over SD-R. In patients who have been exposed to rituximab in the frontline or salvage setting, the addition of rituximab in the peri-transplant setting remains controversial.
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http://dx.doi.org/10.1111/bjh.14731DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5672904PMC
August 2017

Novel chemotherapy-free combination regimen for ibrutinib-resistant mantle cell lymphoma.

Br J Haematol 2018 05 2;181(4):561-564. Epub 2017 Apr 2.

Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

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http://dx.doi.org/10.1111/bjh.14669DOI Listing
May 2018

Haploidentical Transplantation with Post-Transplantation Cyclophosphamide for High-Risk Acute Lymphoblastic Leukemia.

Biol Blood Marrow Transplant 2017 Feb 14;23(2):318-324. Epub 2016 Nov 14.

Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas. Electronic address:

Haploidentical transplantation performed with post-transplantation cyclophosphamide (PTCy)-based graft-versus-host disease (GVHD) prophylaxis has been associated with favorable outcomes for patients with acute myeloid leukemia and lymphomas. However, it remains unclear if such approach is effective for patients with acute lymphoblastic leukemia (ALL). We analyzed outcomes of 109 consecutively treated ALL patients 18 years of age and older at 5 institutions. The median age was 32 years and the median follow-up for survivors was 13 months. Thirty-two patients were in first complete remission (CR1), while the rest were beyond CR1. Neutrophil engraftment occurred in 95% of the patients. The cumulative incidences of grades II to IV and III and IV acute GVHD at day 100 after transplantation were 32% and 11%, respectively, whereas chronic GVHD, nonrelapse mortality, relapse rate, and disease-free survival (DFS) at 1 year after transplantation were 32%, 21%, 27%, and 51%, respectively. Patients in CR1 had 52% DFS at 3 years. These results suggest that haploidentical transplants performed with PTCy-based GVHD prophylaxis provide a very suitable alternative to HLA-matched transplantations for patients with ALL.
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http://dx.doi.org/10.1016/j.bbmt.2016.11.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5517662PMC
February 2017
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