Publications by authors named "Rohtesh S Mehta"

75 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

Nine-Year Follow-up of Patients with Relapsed Follicular Lymphoma after Nonmyeloablative Allogeneic Stem Cell Transplant and Autologous Transplant.

Clin Cancer Res 2021 Aug 11. Epub 2021 Aug 11.

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

Purpose: To compare outcomes between patients with relapsed follicular lymphoma who received a nonmyeloablative allogeneic stem cell transplant (alloSCT) and those who received an autologous transplant (autoSCT).

Patients And Methods: We evaluated 194 patients with follicular lymphoma who received an alloSCT ( = 98) or autoSCT ( = 96) at MD Anderson Cancer Center (Houston, TX). The transplant type used was based on donor availability and by Medicare reimbursement guidelines. Patients who received an alloSCT were enrolled in four consecutive trials in which they received fludarabine, cyclophosphamide (or bendamustine), and rituximab conditioning. autoSCT patients received R-BEAM (rituximab, carmustine, etoposide, cytarabine, and melphalan).

Results: The median follow-up of survivors was 108 months for the alloSCT group and 102 months for the autoSCT group. Overall survival was significantly better for patients who received an alloSCT compared with those who received an autoSCT (62% vs. 46%; = 0.048). Similarly, progression-free survival rates were 52% in patients who received an alloSCT and 31% in those who received an autoSCT ( < 0.001), and the 8-year relapse rates were 11% and 43%, respectively ( < 0.0001). Only three patients in the alloSCT group relapsed beyond 3.5 years. In the alloSCT group, the rates for grade 2 to 4 acute graft-versus-host disease (GVHD), grade 3 to 4 acute GVHD, and extensive chronic GVHD were 22%, 9%, and 38%, respectively. In the autoSCT group, the 8-year incidence of secondary myelodysplasia was 11%. Nonrelapse mortality was similar between the two groups (15% vs. 11% at 8 years; = 0.27).

Conclusions: This study shows that alloSCT is curative and confers superior survival compared with autoSCT in patients with follicular lymphoma.
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http://dx.doi.org/10.1158/1078-0432.CCR-21-1377DOI Listing
August 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

HLA-haploidentical vs matched unrelated donor transplants with posttransplant cyclophosphamide-based prophylaxis.

Blood 2021 07;138(3):273-282

Center for International Blood and Marrow Transplant Research (CIBMTR), Department of Medicine, Medical College of Wisconsin, Milwaukee, WI.

Posttransplant cyclophosphamide (PTCy) graft-versus-host disease (GVHD) prophylaxis has enabled haploidentical (Haplo) transplantation to be performed with results similar to those after matched unrelated donor (MUD) transplantation with traditional prophylaxis. The relative value of transplantation with MUD vs Haplo donors when both groups receive PTCy/calcineurin inhibitor/mycophenolate GVHD prophylaxis is not known. We compared outcomes after 2036 Haplo and 284 MUD transplantations with PTCy GVHD prophylaxis for acute leukemia or myelodysplastic syndrome in adults from 2011 through 2018. Cox regression models were built to compare outcomes between donor types. Recipients of myeloablative and reduced-intensity regimens were analyzed separately. Among recipients of reduced-intensity regimens, 2-year graft failure (3% vs 11%), acute grades 2 to 4 GVHD (hazards ratio [HR], 0.70; P = .022), acute grades 3 and 4 GVHD (HR, 0.41; P = .016), and nonrelapse mortality (HR, 0.43; P = .0008) were lower after MUD than with Haplo donor transplantation. Consequently, disease-free (HR, 0.74; P = .008; 55% vs 41%) and overall (HR, 0.65; P = .001; 67% vs 54%) survival were higher with MUD than with Haplo transplants. Among recipients of myeloablative regimens, day-100 platelet recovery (95% vs 88%) was higher and grades 3 and 4 acute (HR, 0.39; P = .07) and chronic GVHD (HR, 0.66; P = .05) were lower after MUD than with Haplo donor transplantation. There were no differences in graft failure, relapse, nonrelapse mortality, and disease-free and overall survival between donor types with myeloablative conditioning regimens. These data extend and confirm the importance of donor-recipient HLA matching for allogeneic transplantation. A MUD is the preferred donor, especially for transplantations with reduced-intensity conditioning regimens.
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http://dx.doi.org/10.1182/blood.2021011281DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8310426PMC
July 2021

Belumosudil for Chronic Graft-versus-Host Disease (cGVHD) After 2 or More Prior Lines of Therapy: The ROCKstar Study.

Blood 2021 Jul 15. Epub 2021 Jul 15.

Kadmon Corporation, West Chicago, Illinois, United States.

Belumosudil, an investigational oral selective inhibitor of rho-associated coiled-coil-containing protein kinase-2 (ROCK2), reduces type 17 and follicular helper T cells via downregulation of signal transducer and activator of transcription 3 (STAT3) and enhances regulatory T cells via upregulation of signal transducer and activator of transcription 5 (STAT5). Belumosudil may effectively treat patients with cGVHD, a major cause of morbidity and late nonrelapse mortality after an allogeneic hematopoietic cell transplant. This phase 2, randomized, multicenter registration study evaluated belumosudil 200 mg QD (n=66) and 200 mg BID (n=66) in subjects with cGVHD who had received 2 to 5 prior lines of therapy. The primary end point was best overall response rate (ORR). Duration of response (DOR), changes in Lee Symptom Scale score, failure-free survival, corticosteroid dose reductions and overall survival were also evaluated. Overall median follow-up was 14 months. The best ORR (95% CI) of belumosudil 200 mg QD and 200 mg BID was 74% (62%-84%) and 77% (65%-87%), respectively, with high response rates observed in all subgroups. All affected organs demonstrated complete responses. The median DOR was 54 weeks; 44% of subjects have remained on therapy for ≥1 year. Symptom reduction with belumosudil 200 mg QD and 200 mg BID was reported in 59% and 62% of subjects, respectively. Adverse events (AEs) were consistent with those expected in patients with cGVHD receiving corticosteroids and other immunosuppressants. Sixteen subjects (12%) discontinued belumosudil due to possible drug-related AEs. Belumosudil, a promising therapy for cGVHD, was well tolerated with clinically meaningful responses. (Funded by Kadmon Corporation, LLC; ClinicalTrials.gov number, NCT03640481.).
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http://dx.doi.org/10.1182/blood.2021012021DOI Listing
July 2021

Donor clonal hematopoiesis increases risk of acute graft versus host disease after matched sibling transplantation.

Leukemia 2021 Jun 16. Epub 2021 Jun 16.

Department of Genomics Medicine, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA.

Clonal hematopoiesis (CH) is associated with older age and an increased risk of myeloid malignancies and cardiovascular complications. We analyzed donor DNA samples in patients with AML/MDS who underwent first allogeneic stem cell transplant (SCT) to investigate the association between donor CH and transplant outcomes. We performed targeted deep sequencing of 300 genes on donor blood samples and identified CH with the minimum variant allele frequency of 2%. Among 363 donors, 65 (18%) had CH. The most frequently mutated genes were DNMT3A (31 of 65; 48%), TET2 (16 of 65; 25%), PPM1D (5 of 65, 8%), and ASXL1 (7 of 65; 11%). Transplant outcomes: time to neutrophil and platelet recovery, relapse incidence, transplant-related mortality and progression-free survival, were comparable by donor CH. However, risk of grade II-IV and III-IV acute graft versus host disease (aGvHD) at 6 months after transplant was higher with donor CH vs. without donor CH (hazard ratio (HR) = 2.4, 95% Confidence Interval (CI) = 1.6-3.6, p < 0.001 and HR = 3.8, 95% CI = 1.6-8.9, p = 0.003). In this homogenous population of AML/MDS patients, donor CH was associated with increased risk of grade II-IV and III-IV aGvHD. Further studies to investigate the mechanisms of increased aGvHD and therapeutic interventions to improve aGvHD in the context of donor CH are warranted.
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http://dx.doi.org/10.1038/s41375-021-01312-3DOI Listing
June 2021

Post-transplantation donor-derived Sezary syndrome in a patient with A91V PRF1 variant hemophagocytic lymphohistiocytosis.

Am J Hematol 2021 09 28;96(9):E350-E353. Epub 2021 Jun 28.

Department of Dermatology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

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http://dx.doi.org/10.1002/ajh.26266DOI Listing
September 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

Early Adaptive Natural Killer Cell Expansion Is Associated with Decreased Relapse After Autologous Transplantation for Multiple Myeloma.

Transplant Cell Ther 2021 04 17;27(4):310.e1-310.e6. Epub 2020 Dec 17.

Department of Medicine, University of Minnesota, Minneapolis, Minnesota.

Adaptive natural killer (NK) cells are long-lived and exhibit properties of immunologic memory against cytomegalovirus (CMV). We previously reported that expansion of adaptive NK cells after CMV reactivation in recipients of allogeneic hematopoietic cell transplantation (HCT) was associated with a lower rate of relapse of acute myelogenous leukemia. In the present study, we examined the impact of adaptive NK cell expansion in a cohort of 110 individuals who underwent autologous HCT (AHCT) for a lymphoid malignancy (lymphoma or multiple myeloma [MM]). In this cohort, higher absolute numbers of adaptive NK cells (>1.58/μL) at day 28 post-AHCT were associated with significantly decreased risk of relapse in patients with MM. No significant association was seen in patients with lymphoma. Further stratification of MM patients by CMV serostatus found a strong protective effect of adaptive NK cells only in CMV-seropositive individuals. These findings suggest that strategies to increase adaptive NK cells after AHCT may be a therapeutic option in patients with MM.
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http://dx.doi.org/10.1016/j.jtct.2020.10.023DOI Listing
April 2021

Prognostic factors for progression in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia in complete molecular response within 3 months of therapy with tyrosine kinase inhibitors.

Cancer 2021 Aug 1;127(15):2648-2656. Epub 2021 Apr 1.

Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Background: The achievement of a 3-month complete molecular response (CMR) is a major prognostic factor for survival in patients with Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL). However, 25% of patients relapse during therapy with tyrosine kinase inhibitors (TKIs).

Methods: The authors reviewed 204 patients with Ph-positive ALL who were treated between January 2001 and December 2018 using the combination of hyper-CVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) plus a TKI (imatinib, 44 patients [22%]; dasatinib, 88 patients [43%]; or ponatinib, 72 patients [35%]). Progression-free survival (PFS) was defined as the time from the start date of therapy to the date of relapse, death, or last follow-up. Overall survival (OS) was defined as the time from the start date of therapy to the date of death or last follow-up.

Results: Overall, a 3-month CMR was observed in 57% of patients, including 32% of those who received imatinib, 52% of those who received dasatinib, and 74% of those who received ponatinib. The median follow-up was 74 months (imatinib, 180 months; dasatinib, 106 months; ponatinib, 43 months). Among 84 patients in 3-month CMR, 17 (20%) proceeded to undergo allogeneic stem cell transplantation (ASCT). The 5-year PFS and OS rates were 68% and 72%, respectively. By multivariate analysis, ponatinib therapy was the only significant favorable independent factor predicting for progression (P = .028; hazard ratio, 0.388; 95% CI, 0.166-0.904) and death (P = .042; hazard ratio, 0.379; 95% CI, 0.149-0.966). ASCT was not a prognostic factor for PFS and OS by univariate analysis.

Conclusions: In patients with Ph-positive ALL, ponatinib is superior to other types of TKIs in inducing and maintaining a CMR, thus preventing disease progression. ASCT does not improve outcome once a 3-month CMR is achieved.
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http://dx.doi.org/10.1002/cncr.33529DOI Listing
August 2021

Vedolizumab for Steroid Refractory Lower Gastrointestinal Tract Graft-Versus-Host Disease.

Transplant Cell Ther 2021 03 16;27(3):272.e1-272.e5. Epub 2020 Dec 16.

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

Steroid-refractory (SR) lower gastrointestinal (LGI) acute graft-versus-host disease (aGVHD) has poor prognosis, and novel drugs are needed. We describe outcomes of patients with SR-LGI aGVHD treated with vedolizumab. The primary objective was to determine overall response rate (ORR) at days 14, 28, and 56. Secondary outcomes included overall survival (OS), non-relapse mortality and toxicities. Twenty patients, median age 46 years (range, 23-71), were included. All but 2 patients (90%) had grade 3 to 4 aGVHD (45% stage 4, 40% stage 3 LGI). Median time to vedolizumab was 21 days (range, 5-1031) and 13 days (range, 0-533) after diagnosis of LGI aGVHD and SR-LGI aGVHD, respectively. It was given as ≥3rd line (median 3; range 2-6) in 75% after failure of steroids, and additional treatments including ruxolitinib (n = 12) and others. Median follow-up was 17 months (range, 10-34). The days 14, 28 and 56 ORRs were 45% (9/20; complete response [CR] 25%), 35% (7/20; CR 20%), and 25% (5/20; CR 20%), respectively. Among ruxolitinib failures, it was 50% (6/12; CR 25%), 50% (6/12; CR 25%) and 25% (3/12; CR 16.7%), respectively. Fifteen patients died (14 GVHD, 1 leukemia relapse). The actuarial 6-month OS was 35% (95% confidence interval 16-55). No progressive multifocal leukoencephalopathy or infusion reaction occurred. Forty-four infection events (22 viral, 18 bacterial, and 4 fungal) were noted in 16 patients. Vedolizumab was well tolerated and demonstrated potential efficacy even after ruxolitinib failure for SR-LGI aGVHD. Yet the responses were suboptimal, and its use requires further investigation.
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http://dx.doi.org/10.1016/j.jtct.2020.12.011DOI Listing
March 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

Next-Generation Sequencing of in Myeloid Neoplasms Leads to Increased Detection of Germline Alterations.

Front Oncol 2020 28;10:582213. Epub 2021 Jan 28.

Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston, TX, United States.

Previously considered rare, inherited hematologic malignancies are increasingly identified. Germline mutations in the RNA helicase predispose to increased lifetime risks of myeloid neoplasms with disease often occurring later in life which presents challenges for germline recognition. To improve identification of germline , individuals presenting with ≥1 alteration on an institutional MDS/AML next-generation sequencing based panel with at least one at >40% variant allele frequency were flagged for review and genetic counseling referral. Of 5,801 individuals, 90 (1.5%) had ≥1 mutation(s) identified. Thirty-eight (42%) patients with a median age of 66 years were referred for genetic counseling; thirty-one were male (81.5%). Thirty-five (92%) referred patients elected to pursue germline evaluation and in 33/35 (94%) a germline variant was confirmed. Twenty-two patients (66%) with germline variants reported antecedent cytopenias, seven (21%) had a prior history of malignancy, and twenty-seven (82%) reported a family history of cancer. Predictive genetic testing for healthy family members under consideration as stem cell transplant donors was successfully performed in 11 family members, taking an average of 15 days. Near-heterozygous mutations identified on next-generation sequencing, particularly nonsense/frameshift variants or those at recurrent germline "hot spots" are highly suggestive of a germline mutation. Next-generation sequencing screening is a feasible tool to screen unselected myeloid neoplasms for germline mutations, enabling timely and appropriate care.
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http://dx.doi.org/10.3389/fonc.2020.582213DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878971PMC
January 2021

Alternative donor transplantation for myelodysplastic syndromes: haploidentical relative and matched unrelated donors.

Blood Adv 2021 02;5(4):975-983

Center for International Blood and Marrow Transplant Research, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI.

We compared outcomes in 603 patients with myelodysplastic syndrome (MDS) after HLA-haploidentical relative (n = 176) and HLA-matched unrelated (n = 427) donor hematopoietic cell transplantation (HCT) from 2012 to 2017, using the Center for International Blood and Marrow Transplant Research database. All transplantations used reduced-intensity conditioning regimens. Total-body irradiation plus cyclophosphamide and fludarabine was the predominant regimen for HLA-haploidentical relative donor HCT, and graft-versus-host disease (GVHD) prophylaxis was uniformly posttransplantation cyclophosphamide, calcineurin inhibitor, and mycophenolate. Fludarabine with busulfan or melphalan was the predominant regimen for HLA-matched unrelated donor HCT, and GVHD prophylaxis was calcineurin inhibitor with mycophenolate or methotrexate. Results of multivariate analysis revealed higher relapse (hazard ratio [HR], 1.56; P = .0055; 2-year relapse rate, 48% vs 33%) and lower disease-free survival (DFS) rates after HLA-haploidentical relative donor HCT (HR, 1.29; P = .042; 2-year DFS, 29% vs 36%). However, overall survival (OS) rates did not differ between donor type (HR, 0.94; P = .65; 2-year OS, 46% for HLA-haploidentical and 44% for HLA-matched unrelated donor HCT) because of mortality associated with chronic GVHD. Acute grade 2 to 4 GVHD (HR, 0.44; P < .0001) and chronic GVHD (HR, 0.36; P < .0001) were lower after HLA-haploidentical relative donor HCT. By 2 years, probability of death resulting from chronic GVHD was lower after HLA-haploidentical relative compared with HLA-matched unrelated donor HCT (6% vs 21%), negating any potential survival advantage from better relapse control. Both donor types extend access to transplantation for patients with MDS; strategies for better relapse control are desirable for HLA-haploidentical relative donor HCT, and effective GVHD prophylaxis regimens are needed for unrelated donor HCT.
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http://dx.doi.org/10.1182/bloodadvances.2020003654DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7903230PMC
February 2021

Fractionated busulfan myeloablative conditioning improves survival in older patients with acute myeloid leukemia and myelodysplastic syndrome.

Cancer 2021 May 20;127(10):1598-1605. Epub 2021 Jan 20.

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

Background: A myeloablative conditioning regimen can be safely given to older patients and those with comorbidities without increasing nonrelapse mortality (NRM) by fractionating the dose of intravenous busulfan. How this approach compares in efficacy with traditional, nonfractionated, lower dose regimens is unknown.

Methods: Outcomes were compared in patients with acute myeloid leukemia (AML) or myelodysplastic syndrome who received either myeloablative, fractionated busulfan (f-Bu) dosed to achieve an area under the curve of 20,000 μmol per minute (f-Bu20K) over 2 weeks (n = 84) or a standard, nonfractionated, lower busulfan dose regimen of 16,000 μmol per minute (Bu16K) over 4 days (n = 78). Both groups also received fludarabine 40 mg/m intravenously for 4 days. Graft-versus-host disease prophylaxis was tacrolimus and methotrexate. Patients in the Bu16K group who had unrelated donors also received antithymocyte globulin. The primary endpoint was progression-free survival.

Results: Roughly one-half of the patients were aged >65 years, approximately 40% had poor-risk cytogenetics, approximately 40% of those with AML were not in complete remission, and approximately 40% had a comorbidity index >3. At 2 years, progression-free survival was significantly improved in the f-Bu20K group compared with the Bu16K group (45% vs 24%, respectively; hazard ratio [HR], 0.6; 95% CI, 0.4-0.8; P = .004). This was because of a significant reduction in progression (34% vs 59%, respectively; HR, 0.5; 95% CI, 0.3-0.8; P = .003) without any increase in NRM (21% vs 15%, respectively; HR, 1.4; 95% CI, 0.7-3; P = .3), which resulted in improved overall survival (51% vs 31%, respectively; HR, 0.6; 95% CI, 0.3-0.9; P = .01).

Conclusions: A myeloablative, fractionated busulfan regimen reduces relapse and improves survival without increasing NRM in older patients with AML and myelodysplastic syndrome.
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http://dx.doi.org/10.1002/cncr.33383DOI Listing
May 2021

Randomized phase II trial of extracorporeal phototherapy and steroids vs. steroids alone for newly diagnosed acute GVHD.

Bone Marrow Transplant 2021 06 4;56(6):1316-1324. Epub 2021 Jan 4.

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

Steroids remain the initial therapy for acute graft-vs.-host disease (AGVHD). Strategies to improve response and minimize steroid exposure are needed. We report results of a randomized, adaptive, Bayesian-designed, phase II trial of prednisone with or without extracorporeal photopheresis (ECP) as an initial therapy for patients with newly diagnosed AGVHD. The primary endpoint was success at day 56 defined as: alive, in remission, achieving AGVHD response without additional therapy, and on <1 mg/kg at day 28 and <0.5 mg/kg on day 56 of steroids. Eighty-one patients were randomized to the ECP arm (n = 51) or steroids alone (n = 30). Median age was 54 years (range: 17-75); 90% had grade II AGVHD and 10% had grades III and IV AGVHD, with skin (85%), upper (22%)/lower (22%) gastrointestinal, and liver (10%) involvement. The ECP arm had a higher probability of success (0.815) and exceeded the predefined threshold for determining the investigational arm promising. ECP was potentially more beneficial than steroids-alone in skin-only AGVHD (response rate: 72% vs. 57%, respectively) than for visceral-organ AGVHD (47% vs. 43%, respectively). The addition of ECP to steroids may result in higher GVHD response as initial therapy for AGVHD, especially for patients with skin-only involvement.
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http://dx.doi.org/10.1038/s41409-020-01188-4DOI Listing
June 2021

Optimizing the Conditioning Regimen for Hematopoietic Cell Transplant in Myelofibrosis: Long-Term Results of a Prospective Phase II Clinical Trial.

Biol Blood Marrow Transplant 2020 08 11;26(8):1439-1445. Epub 2020 May 11.

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

Optimal conditioning regimens for older patients with myelofibrosis undergoing allogeneic hematopoietic cell transplant are not known. Likewise, the role of dose intensity is not clear. We conducted a nonrandomized, prospective, phase II trial using low-dose, later escalated to high-dose (myeloablative conditioning), busulfan with fludarabine (Bu-Flu) in myelofibrosis patients up to age 74 years. The first 15 patients received i.v. busulfan 130 mg/m/day on days -3 and -2 ("low dose"); 31 patients received high-dose conditioning, either 100 mg/m/day (days -5 to -2; n = 4) or pharmacokinetic-guided area under the curve of 4000 μmol/min (days -5 to -2; n = 27). The primary endpoint was day 100 nonrelapse mortality (NRM). Median age was 58 years (interquartile range [IQR], 53-63). Dynamic international prognostic scoring system-plus was intermediate (n = 28) or high (n = 18). Donors were related (n = 19) or unrelated (n = 27). Cumulative incidence of NRM was 9.7% (95% confidence interval [CI], 0-20.3) at day 100 and at 3 years in the high-dose group and 0% in the low-dose group at day 100, which increased to 20% (95% CI, 0-41.9) at 3 years. With a median follow-up of 5.1 years (IQR, 3.8-6), 3-year relapse was 32.3% (95% CI, 15.4-49.1) in high dose versus 53.3% (95% CI, 26.6-80.1) in low dose. Event-free survival was 58% (95% CI, 43-78) versus 27% (95% CI, 12-62), and overall survival was 74% (95% CI, 60-91) versus 60% (95% CI, 40-91). In multivariate analysis, high-dose busulfan had a trend toward lower relapse (hazard ratio, .44; 95% CI, .18-1.07; P = .07), with no impact on NRM. Intensifying the Bu-Flu regimen using pharmacokinetic-monitoring appears to be promising in reducing relapse without increasing NRM.
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http://dx.doi.org/10.1016/j.bbmt.2020.03.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7547798PMC
August 2020

Composite GRFS and CRFS Outcomes After Adult Alternative Donor HCT.

J Clin Oncol 2020 06 4;38(18):2062-2076. Epub 2020 May 4.

Division of Clinical Hematology, Hospital de la Santa Creu I Sant Pau, Barcelona, Spain.

Purpose: There is no consensus on the best choice of an alternative donor (umbilical cord blood [UCB], haploidentical, one-antigen mismatched [7/8]-bone marrow [BM], or 7/8-peripheral blood [PB]) for hematopoietic cell transplantation (HCT) for patients lacking an HLA-matched related or unrelated donor.

Methods: We report composite end points of graft-versus-host disease (GVHD)-free relapse-free survival (GRFS) and chronic GVHD (cGVHD)-free relapse-free survival (CRFS) in 2,198 patients who underwent UCB (n = 838), haploidentical (n = 159), 7/8-BM (n = 241), or 7/8-PB (n = 960) HCT. All groups were divided by myeloablative conditioning (MAC) intensity or reduced intensity conditioning (RIC), except haploidentical group in which most received RIC. To account for multiple testing, < .0071 in multivariable analysis and < .00025 in direct pairwise comparisons were considered statistically significant.

Results: In multivariable analysis, haploidentical group had the best GRFS, CRFS, and overall survival (OS). In the direct pairwise comparison of other groups, among those who received MAC, there was no difference in GRFS or CRFS among UCB, 7/8-BM, and 7/8-PB with serotherapy (alemtuzumab or antithymocyte globulin) groups. In contrast, the 7/8-PB without serotherapy group had significantly inferior GRFS, higher cGVHD, and a trend toward worse CRFS (hazard ratio [HR], 1.38; 95% CI, 1.13 to 1.69; = .002) than the 7/8-BM group and higher cGVHD and trend toward inferior CRFS (HR, 1.36; 95% CI, 1.14 to 1.63; = .0006) than the UCB group. Among patients with RIC, all groups had significantly inferior GRFS and CRFS compared with the haploidentical group.

Conclusion: Recognizing the limitations of a registry retrospective analysis and the possibility of center selection bias in choosing donors, our data support the use of UCB, 7/8-BM, or 7/8-PB (with serotherapy) grafts for patients undergoing MAC HCT and haploidentical grafts for patients undergoing RIC HCT. The haploidentical group had the best GRFS, CRFS, and OS of all groups.
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http://dx.doi.org/10.1200/JCO.19.00396DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7302955PMC
June 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

Posttransplantation cyclophosphamide improves transplantation outcomes in patients with AML/MDS who are treated with checkpoint inhibitors.

Cancer 2020 05 3;126(10):2193-2205. Epub 2020 Mar 3.

Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Background: There have been concerns regarding increased peritransplantation complications, especially severe acute graft-versus-host disease (aGVHD), in patients with prior use of checkpoint inhibitors (CPI) before hematopoietic stem cell transplantation (HSCT).

Methods: The authors performed a retrospective study of 43 patients with acute myeloid leukemia and/or myelodysplastic syndromes who were treated with an antiprogrammed cell death protein 1 (PD-1) (32 patients) or anticytotoxic T-lymphocyte-associated protein 4 (CTLA-4) (9 patients) blockade or both (2 patients) prior to HSCT with the primary outcome of aGVHD by day 100 after HSCT. Outcome analyses were stratified by GVHD prophylaxis as use of post-HSCT cyclophosphamide (PTCy) (22 patients) or not (non-PTCy) (21 patients).

Results: The PTCy group demonstrated a trend toward lower grade 3 to 4 aGVHD when compared with the non-PTCy group (5% vs 22%), although the rates of grade 2 to 4 aGVHD were comparable (49% vs 56%). The interval between CPI and HSCT did not appear to impact the incidence of aGVHD. However, a higher incidence of grade 3 to 4 aGVHD was observed in patients who received >4 treatments of CPI prior to HSCT if they were not given PTCy as GVHD prophylaxis (43% vs 12%). Matched control analyses using patients with no prior use of CPI confirmed the increase in grade 3 to 4 aGVHD with those agents. However, that increased risk was limited to patients who did not receive PTCy and was not observed in patients who received PTCy as GVHD prophylaxis. Despite persistent improvement in GVHD with the use of PTCy, disease control was not compromised and progression-free survival at 1 year was found to be superior for patients treated with PTCy compared with those not receiving PTCy among patients with prior use of CPI (55% vs 22%).

Conclusions: The results of the current study indicated that HSCT with prior use of CPI appears feasible in patients with acute myeloid leukemia and/or myelodysplastic syndromes and the use of PTCy as GVHD prophylaxis improves outcomes.
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http://dx.doi.org/10.1002/cncr.32796DOI Listing
May 2020

Editorial: Cellular Therapies in Cancer.

Front Immunol 2019 27;10:2788. Epub 2019 Nov 27.

Department of Stem Cell Transplant and Cellular Therapy, MD Anderson Cancer Center, Houston, TX, United States.

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http://dx.doi.org/10.3389/fimmu.2019.02788DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6890829PMC
November 2020

A novel immature natural killer cell subpopulation predicts relapse after cord blood transplantation.

Blood Adv 2019 12;3(23):4117-4130

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

Natural killer (NK) cells are highly heterogeneous, with vast phenotypic and functional diversity at the single-cell level. They are involved in the innate immune response against malignant and virus-infected cells. To understand the effect of NK diversity during immune recovery on the antitumor response after cord blood transplantation (CBT), we used high-dimensional mass cytometry and the metrics of NK cell diversity to study the NK cell repertoire in serial samples from 43 CBT recipients. A higher-diversity index based on single-cell combinatorial phenotypes was significantly associated with a lower risk for relapse after CBT (P = .005). Cytomegalovirus reactivation was a major factor in the development of a more diverse NK repertoire after CBT. Notably, we identified a group of patients whose CB-derived NK cells after transplantation possessed an immature phenotype (CB-NKim), characterized by poor effector function and a low diversity index. Frequencies of CB-NKim of 11.8% or higher during the early post-CBT recovery phase were highly predictive for relapse (area under the curve [AUC], 0.979), a finding that was validated in a second independent cohort of patients (n = 25; AUC, 0.977). Moreover, we showed that the maturation, diversity, and acquisition of effector function by CB-NKim early after CBT were driven by interleukin 15. Our data indicate that the diversity of the NK cell repertoire after CBT contributes importantly to the risk for subsequent relapse. We suggest that the use of diversity metrics and high-dimensional mass cytometry may be useful tools in predicting clinical outcomes and informing the design of therapeutic strategies to prevent relapse after CBT.
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http://dx.doi.org/10.1182/bloodadvances.2019000835DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6963241PMC
December 2019

Neurotoxic events associated with BCR-ABL1 tyrosine kinase inhibitors: a case series.

Leuk Lymphoma 2019 12 27;60(13):3292-3295. Epub 2019 Jun 27.

Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

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http://dx.doi.org/10.1080/10428194.2019.1633635DOI Listing
December 2019

Retrospective Review of the Use of High-Dose Cyclophosphamide, Bortezomib, Doxorubicin, and Dexamethasone for the Treatment of Multiple Myeloma and Plasma Cell Leukemia.

Clin Lymphoma Myeloma Leuk 2019 09 17;19(9):560-569. Epub 2019 May 17.

Department of Lymphoma/Myeloma, The University of Texas M.D. Anderson Cancer Center, Houston, TX. Electronic address:

Background: Multiple myeloma (MM) usually follows a clinical course leading to refractoriness and limited treatment options in advanced stages, which might need bridge therapies to either autologous stem cell transplantation or novel therapies. We report our experience with the high-dose chemotherapy mCBAD (modified cyclophosphamide, bortezomib, doxorubicin, and dexamethasone) regimen in newly diagnosed MM (NDMM), relapsed/refractory MM (RRMM), and plasma cell leukemia (PCL) patients.

Patients And Methods: We searched our electronic records database for MM patients who received mCBAD from 2010 to 2016 for 28-day cycles of cyclophosphamide 350 mg/m intravenously (I.V.) twice daily with mesna 400 mg/m I.V. daily (days 1-4), bortezomib 1.3 mg/m subcutaneously/I.V. (days 1, 4, 8, 11), doxorubicin 9 mg/m daily continuous infusion (days 1-4), dexamethasone 40 mg orally daily (on days 1-4, 9-12, 17-20). International Myeloma Working Group (IMWG) criteria were used for response assessment and diagnosis. Descriptive statistics, Fisher exact test, χ, Wilcoxon rank sum, and Kaplan-Meier were used for statistical purposes.

Results: One hundred forty patients met the inclusion criteria. A median of 2 cycles of therapy was administered. The overall response rate was 85% in patients with RRMM (n = 116) and 100% in NDMM (n = 13) and PCL (n = 11) patients. Respective median progression-free survival (mPFS) for NDMM, PCL, and RRMM were 19.61 months (95% confidence interval [CI], 5.26 to not applicable [NA]), 7.56 months (95% CI, 4.7 to NA), and 4.64 months (95% CI, 3.75-6.73). Patients with RRMM who used mCBAD as a bridge to autologous transplant (36.2%) had mPFS (11.48 months; 95% CI, 7.52-15.9 months) compared with those who did not (mPFS: 3.19 months; 95% CI, 2.4-3.75 months). Cytopenias occurred in more than 90% of patients, and febrile neutropenia was noted in 26%. All cases of treatment-related mortality (8%) occurred in patients with RRMM, except for 1 patient with PCL.

Conclusion: mCBAD results in high response rates in myeloma and PCL, however, with high treatment-related mortality. Its use in RRMM should be limited to patients who have immediate need for therapy without other treatment options and who have good performance status (score of 0-1) or NDMM if novel agents are not available depending on practice setting. mCBAD can be a treatment option for patients with PCL.
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http://dx.doi.org/10.1016/j.clml.2019.05.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6713607PMC
September 2019

GRFS and CRFS in alternative donor hematopoietic cell transplantation for pediatric patients with acute leukemia.

Blood Adv 2019 05;3(9):1441-1449

Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.

We report graft-versus-host disease (GVHD)-free relapse-free survival (GRFS) (a composite end point of survival without grade III-IV acute GVHD [aGVHD], systemic therapy-requiring chronic GVHD [cGVHD], or relapse) and cGVHD-free relapse-free survival (CRFS) among pediatric patients with acute leukemia (n = 1613) who underwent transplantation with 1 antigen-mismatched (7/8) bone marrow (BM; n = 172) or umbilical cord blood (UCB; n = 1441). Multivariate analysis was performed using Cox proportional hazards models. To account for multiple testing, < .01 for the donor/graft variable was considered statistically significant. Clinical characteristics were similar between UCB and 7/8 BM recipients, because most had acute lymphoblastic leukemia (62%), 64% received total body irradiation-based conditioning, and 60% received anti-thymocyte globulin or alemtuzumab. Methotrexate-based GVHD prophylaxis was more common with 7/8 BM (79%) than with UCB (15%), in which mycophenolate mofetil was commonly used. The univariate estimates of GRFS and CRFS were 22% (95% confidence interval [CI], 16-29) and 27% (95% CI, 20-34), respectively, with 7/8 BM and 33% (95% CI, 31-36) and 38% (95% CI, 35-40), respectively, with UCB ( < .001). In multivariate analysis, 7/8 BM vs UCB had similar GRFS (hazard ratio [HR], 1.12; 95% CI, 0.87-1.45; = .39), CRFS (HR, 1.06; 95% CI, 0.82-1.38; = .66), overall survival (HR, 1.07; 95% CI, 0.80-1.44; = .66), and relapse (HR, 1.44; 95% CI, 1.03-2.02; = .03). However, the 7/8 BM group had a significantly higher risk for grade III-IV aGVHD (HR, 1.70; 95% CI, 1.16-2.48; = .006) compared with the UCB group. UCB and 7/8 BM groups had similar outcomes, as measured by GRFS and CRFS. However, given the higher risk for grade III-IV aGVHD, UCB might be preferred for patients lacking matched donors.
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http://dx.doi.org/10.1182/bloodadvances.2018030171DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6517657PMC
May 2019

Cord Blood Expansion: A Clinical Advance.

J Clin Oncol 2019 02 21;37(5):363-366. Epub 2018 Dec 21.

1 The University of Texas MD Anderson Cancer Center, Houston, TX.

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http://dx.doi.org/10.1200/JCO.18.01789DOI Listing
February 2019
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