Publications by authors named "Lori Muffly"

78 Publications

Chimeric Antigen Receptor-T Cell Therapy in Adults with B-Cell Acute Lymphoblastic Leukemia: A Systematic Review.

Blood Adv 2021 Oct 5. Epub 2021 Oct 5.

Stanford University, Stanford, Ohio, United States.

Chimeric antigen receptor T-cell (CAR-T) therapy has transformed treatment paradigms for relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL) in children and younger adults. We performed a systematic review to investigate the published literature on efficacy and toxicity of CAR-T therapy in adults with r/r B-ALL. We searched MEDLINE, Embase and Cochrane Library for prospective, interventional studies and included published studies of ≥5 patients with median age at enrollment of ≥ 18 years. Risk of bias was assessed using a modified Institute of Health Economics tool. A total of 2566 records were assessed; 16 studies involving 489 patients were included in the final analysis. The mean CR rate was 81% and MRD negative remission rate was 81% at 4 weeks post CAR-T infusion. With median follow-up across studies of 24 months the cumulative 12-month probability of PFS and OS were 37% (95% CI 26-48%) and 57% (95% CI 49-65%), respectively. Relapse occurred in 40.3%; target antigen was retained in 73.2% of relapses. Across studies, any grade of CRS occurred in 82% (95% CI 61-95%) and grade 3 or higher CRS in 27% (95% CI 18-36%). Neurotoxicity of any grade occurred in 34% (95% CI 24-47%) and grade 3 or higher in 14% (95% CI 1-25%). In summary, CAR-T therapy achieves high early remission rates in adults with r/r B-ALL and represents a significant improvement over traditional salvage chemotherapy. Relapses are common and durable response remains a challenge.
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http://dx.doi.org/10.1182/bloodadvances.2020003482DOI Listing
October 2021

Measurable residual disease status and FLT3 inhibitor therapy in patients with FLT3-ITD mutated AML following allogeneic hematopoietic cell transplantation.

Bone Marrow Transplant 2021 Sep 28. Epub 2021 Sep 28.

Department of Medicine, Division of Blood and Marrow Transplantation, Stanford University School of Medicine, Stanford, CA, USA.

Measurable residual disease (MRD) is associated with poor prognosis in acute myeloid leukemia (AML), even after allogeneic hematopoietic cell transplantation (HCT). New next-generation sequencing (NGS) methods have emerged as a highly sensitive and specific method to detect MRD. In addition to defining the role of post-HCT MRD monitoring in FLT3-ITD mutated AML, there is great interest in the optimal use of oral FLT3 tyrosine kinase inhibitors (FLT3 inhibitors) to maintain remission following HCT. In this study, we evaluated the clinical impact of sensitive FLT3 MRD testing early after HCT and maintenance FLT3 inhibitor use at our transplant center. We found that there was a trend towards inferior progression-free survival (PFS) for patients with early post-HCT MRD, but that overall survival (OS) was not significantly impacted by MRD. The use of maintenance FLT3 inhibitors led to a significantly superior PFS and OS in our cohort, and improved PFS and OS in both MRD-negative and MRD-positive patients. Altogether, our results demonstrate the prognostic significance of NGS-based MRD monitoring for FLT3-ITD and the ability of post-HCT maintenance therapy to prevent relapse and death in FLT3-ITD mutated AML.
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http://dx.doi.org/10.1038/s41409-021-01475-8DOI Listing
September 2021

Haploidentical vs. sibling, unrelated, or cord blood hematopoietic cell transplantation for acute lymphoblastic leukemia.

Blood Adv 2021 Sep 21. Epub 2021 Sep 21.

University of Virginia, Charlottesville, Virginia, United States.

The role of haploidentical hematopoietic cell transplantation (HCT) using post-transplant cyclophosphamide (PTCy) for acute lymphoblastic leukemia (ALL) is being defined. We performed a retrospective, multivariate analysis comparing outcomes of HCT approaches by donor for adults with ALL in remission. The primary objective was to compare overall survival (OS) between haploidentical HCT using PTCy and HLA-matched sibling donor (MSD), 8/8 HLA-matched unrelated donor (MUD) , 7/8 HLA-matched UD, or umbilical cord blood (UCB) HCT. Comparing haploidentical to MSD HCT, OS, leukemia-free survival (LFS), non-relapse mortality (NRM), relapse, and acute graft-versus-host disease (aGVHD) were not different but chronic GVHD (cGVHD) was higher with MSD HCT. Compared to MUD HCT, OS, LFS, and relapse were not different but MUD HCT had increased NRM (HR 1.42, P=0.02), grade 3-4 aGVHD (HR 1.59, P=0.005), and cGVHD. Compared to 7/8 UD HCT, LFS and relapse were not different, but 7/8 UD HCT had worse OS (HR 1.38, P=0.01) and increased NRM (HR 2.13, P=<0.001), grade 3-4 aGVHD (HR 1.86, P=0.003), and cGVHD (HR 1.72, P=<0.001). Compared to UCB HCT, late OS , late LFS, relapse, and cGVHD were not different but UCB HCT had worse early OS (≤18 months, HR 1.93, P<0.001), worse early LFS (HR 1.40, P=0.007) and increased incidences of NRM (HR 2.08, P<0.001) and grade 3-4 aGVHD (HR 1.97, P<0.001). Haploidentical HCT using PTCy showed no difference in survival but less GVHD compared to traditional MSD and MUD HCT and is the preferred alternative donor HCT option for adults with ALL in CR.
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http://dx.doi.org/10.1182/bloodadvances.2021004916DOI Listing
September 2021

Incidence and Risk Factors Associated with Bleeding and Thrombosis Following Chimeric Antigen Receptor T Cell Therapy.

Blood Adv 2021 Sep 14. Epub 2021 Sep 14.

Stanford University, Stanford, California, United States.

Bleeding and thrombotic events are an emerging toxicity associated with chimeric antigen receptor (CAR) therapies. To determine their incidence, we retrospectively analyzed consecutive adult patients (n=127) with large B-cell lymphoma (LBCL) or B-cell acute lymphoblastic leukemia (B-ALL) treated between 2017-2020 with axicabtagene ciloleucel (axi-cel) (N=89) or a bispecific CD19/CD22 CAR (N=38). 12 (9.4%) and 8 (6.3%) patients developed bleeding and thrombosis within first 3 months, respectively. In the axi-cel subgroup, these occurred in 11.2% and 6.7%, respectively. Bleeding occurred between days 8-30 (median 17.5), and thrombosis between days 2-91 (median 29). Bleeding sites included genitourinary (N=6), soft tissue (N=2), intracranial (N=2), gastrointestinal (N=1), pulmonary (N=1), and were associated with features of consumptive coagulopathy. On univariate analysis, patients with bleeding were older (median 72 vs. 60 yrs, P<0.01), had lower baseline platelets (86 vs. 178 K/uL, P<0.01), lower platelet nadir after CAR-T (median 17.5 vs. 48 K/uL; P<0.01), lower fibrinogen nadir (median 122 vs. 340 ug/mL; P<0.01) and elevated LDH (P=0.01). ICANS grade ≥3 was associated with increased bleeding (50% vs. 15%; P=0.01), thrombosis (50% vs. 16%; P=0.04), PT prolongation, hypofibrinogenemia and elevated D-dimer. A paucity of events limited multivariate analysis, however low pre-treatment platelets were associated with bleeding in a multivariate logistic regression model. Patients with thrombocytopenia or severe ICANS are at increased risk of bleeding complications and should be closely monitored particularly within the first month after CAR therapy. Future studies in larger cohorts should assess risk factors for systemic coagulopathies in CAR-T therapy, including their association with neurotoxicity.
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http://dx.doi.org/10.1182/bloodadvances.2021004716DOI Listing
September 2021

Frontline treatment patterns and outcomes among older adults with acute myeloid leukemia: A population-based analysis in the modern era.

Cancer 2021 Aug 26. Epub 2021 Aug 26.

Division of Blood and Marrow Transplantation, Department of Medicine, Stanford University Medical Center, Stanford, California.

Background: Traditionally, conventional induction chemotherapy has been the primary frontline treatment for acute myeloid leukemia (AML); however, older adults are often poor chemotherapy candidates. Recently, several nonconventional frontline AML regimens, including hypomethylating agents, the BCL-2 inhibitor venetoclax, and targeted therapies, have emerged, and they may offer new options for older adults. This study was aimed at describing treatment patterns and outcomes of older adult AML in a modern population-based cohort.

Methods: This study evaluated patients aged ≥60 years with a first primary diagnosis of AML (2014-2017) in the California Cancer Registry linked to inpatient hospitalizations. Multivariable regression examined factors associated with the frontline treatment regimen and survival.

Results: In all, 3068 patients were included; 36% received frontline therapy with a conventional chemotherapy backbone, 42% received nonconventional therapy, and 22% received no treatment. The use of nonconventional therapy increased over time from 38% of patients in 2014 to 47% in 2017 (P < .001). In multivariable analyses, receipt of treatment was associated with an age younger than 80 years, fewer than 2 comorbidities, and care at a National Cancer Institute-designated cancer center (NCI-CC). Compared with conventional chemotherapy, nonconventional therapy was associated with Black race/ethnicity, public health insurance, fewer hospital admissions, and fewer inpatient days. Receiving frontline therapy at an NCI-CC was independently associated with superior overall survival.

Conclusions: Using a population-based approach, this study has demonstrated that patterns of care for frontline AML treatment in older adults are changing, with increasing use of nonconventional therapies. A significant proportion of older adults remain untreated. At the population level, there remain opportunities to increase therapy access for older adults with AML.
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http://dx.doi.org/10.1002/cncr.33873DOI Listing
August 2021

Concordance of peripheral blood and bone marrow measurable residual disease in adult acute lymphoblastic leukemia.

Blood Adv 2021 08;5(16):3147-3151

Division of Blood and Marrow Transplantation.

Monitoring of measurable residual disease (MRD) is essential to the management of acute lymphoblastic leukemia (ALL) and is typically performed through repeated bone marrow (BM) assessments. Using a next-generation sequencing (NGS) MRD platform, we performed a prospective observational study evaluating the correlation between peripheral blood (PB) and BM MRD in adults with ALL receiving cellular therapies (hematopoietic cell transplantation [HCT] and chimeric antigen receptor T-cell [CAR-T] therapies). Among the study cohort (N = 69 patients; 126 paired PB/BM samples), we found strong correlation between PB and BM MRD (r = 0.87; P < .001), with a sensitivity and specificity of MRD detection in the PB of 87% and 90%, respectively, relative to MRD in the BM. MRD became detectable in the PB in 100% of patients who subsequently relapsed following HCT, with median time from MRD+ to clinical relapse of 90 days, and in 85% of patients who relapsed following CAR T, with median time from MRD+ to clinical relapse of 60 days. In adult patients with ALL undergoing cellular therapies, we demonstrate strong concordance between NGS-based MRD detected in the PB and BM. Monitoring of ALL MRD in the PB appears to be an adequate alternative to frequent invasive BM evaluations in this clinical setting.
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http://dx.doi.org/10.1182/bloodadvances.2021004234DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8405199PMC
August 2021

CAR T cells with dual targeting of CD19 and CD22 in adult patients with recurrent or refractory B cell malignancies: a phase 1 trial.

Nat Med 2021 08 26;27(8):1419-1431. Epub 2021 Jul 26.

Division of Blood and Marrow Transplantation and Cellular Therapy, Stanford University School of Medicine, Stanford, CA, USA.

Despite impressive progress, more than 50% of patients treated with CD19-targeting chimeric antigen receptor T cells (CAR19) experience progressive disease. Ten of 16 patients with large B cell lymphoma (LBCL) with progressive disease after CAR19 treatment had absent or low CD19. Lower surface CD19 density pretreatment was associated with progressive disease. To prevent relapse with CD19 or CD19 disease, we tested a bispecific CAR targeting CD19 and/or CD22 (CD19-22.BB.z-CAR) in a phase I clinical trial ( NCT03233854 ) of adults with relapsed/refractory B cell acute lymphoblastic leukemia (B-ALL) and LBCL. The primary end points were manufacturing feasibility and safety with a secondary efficacy end point. Primary end points were met; 97% of products met protocol-specified dose and no dose-limiting toxicities occurred during dose escalation. In B-ALL (n = 17), 100% of patients responded with 88% minimal residual disease-negative complete remission (CR); in LBCL (n = 21), 62% of patients responded with 29% CR. Relapses were CD19 in 50% (5 out of 10) of patients with B-ALL and 29% (4 out of 14) of patients with LBCL but were not associated with CD22 disease. CD19/22-CAR products demonstrated reduced cytokine production when stimulated with CD22 versus CD19. Our results further implicate antigen loss as a major cause of CAR T cell resistance, highlight the challenge of engineering multi-specific CAR T cells with equivalent potency across targets and identify cytokine production as an important quality indicator for CAR T cell potency.
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http://dx.doi.org/10.1038/s41591-021-01436-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8363505PMC
August 2021

Outcomes after delayed and second autologous stem cell transplant in patients with relapsed multiple myeloma.

Bone Marrow Transplant 2021 Jun 23. Epub 2021 Jun 23.

Department of Medicine, Stanford University, Stanford, CA, USA.

We evaluated the outcomes of 168 patients undergoing delayed or second autologous stem cell transplant (ASCT) for relapsed multiple myeloma (MM) from 2010 to 2019. Overall, 21% (n = 35) patients had received a prior transplant and 69% (n = 116) underwent transplant at first relapse. Overall, 27% patients had high-risk cytogenetics and 15% had ISS stage III disease. Stem cell collection was performed after relapse in 72% and 35% of patients received maintenance therapy. Median PFS from salvage treatment and transplant were 28 and 19 months, respectively. Median OS from salvage treatment and transplant was 69 and 55 months. Multivariate analysis revealed that ASCT in first relapse was associated with superior PFS (HR 0.63, p = 0.03) and OS (HR 0.59, p = 0.04) compared to later lines of therapy. In addition, PFS of ≥36 months with prior therapy was associated with improved PFS (HR 0.62, p = 0.04) and OS (HR 0.41, p = 0.01). Ninety-five patients underwent delayed transplant at first relapse, median PFS and OS from start of therapy was 30 and 69 months, and median OS from diagnosis was 106 months. These data may serve as a guide when counseling patients undergoing ASCT for relapsed MM and provide a benchmark in designing clinical trials of transplantation/comparative treatments for relapsed MM.
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http://dx.doi.org/10.1038/s41409-021-01371-1DOI Listing
June 2021

Chronic medical conditions and late effects after acute myeloid leukaemia in adolescents and young adults: a population-based study.

Int J Epidemiol 2021 05;50(2):663-674

Division of Hematology and Oncology, Center for Oncology Hematology Outcomes Research and Training (COHORT), University of California, Davis, Sacramento, CA, USA.

Background: Curative-intent treatment of acute myeloid leukaemia (AML) can lead to multiple chronic medical conditions ('late effects'). Little is known about the burden of late effects in adolescent and young adult (AYA, 15-39 years) survivors of AML. We aimed to estimate the cumulative incidence and investigate the main predictors of late effects among these patients.

Methods: During 1996-2012, 1168 eligible AYAs with AML who survived ≥2 years after diagnosis were identified in the California Cancer Registry. Late effects were reported from State hospital discharge data, and patients were followed through 2014. Hazard ratios and 95% confidence intervals of late effects occurrence were estimated using Cox proportional hazard models, adjusted for sociodemographic and clinical factors.

Results: The most common late effects at 10 years after diagnosis were: endocrine (26.1%), cardiovascular (18.6%) and respiratory (6.6%), followed by neurologic (4.9%), liver/pancreatic (4.3%), renal (3.1%), avascular necrosis (2.7%) and second primary malignancies (2.4%). Of 1168 survivors, 547 (46.8%) received a haematopoietic stem cell transplant (HSCT). After multivariable adjustments, AYAs who underwent HSCT or had a non-favourable risk AML experienced ∼2-fold or higher increased likelihood of all late effects. Additionally, AYAs of Hispanic, Black or Asian/Pacific Islander (vs non-Hispanic White) race/ethnicity and those who resided in lower socio-economic neighbourhoods were at higher risk of numerous late effects.

Conclusions: Our findings underscore the need for long-term surveillance for the prevention, early detection and treatment of late effects, and can inform the development of AYA-focused consensus-based guidelines that will ultimately improve the quality of life and survival of these young vulnerable patients.
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http://dx.doi.org/10.1093/ije/dyaa184DOI Listing
May 2021

Stem Cell Mobilization in Multiple Myeloma: Comparing Safety and Efficacy of Cyclophosphamide +/- Plerixafor versus Granulocyte Colony-Stimulating Factor +/- Plerixafor in the Lenalidomide Era.

Transplant Cell Ther 2021 07 26;27(7):590.e1-590.e8. Epub 2021 Apr 26.

Stanford Cancer Institute, Stanford, California; Division of Blood and Marrow Transplantation and Cellular Therapy, Department of Medicine, Stanford University, Stanford, California. Electronic address:

Growth factor and chemotherapy-based stem cell mobilization strategies are commonly used to treat patients with multiple myeloma. We retrospectively compared 398 patients mobilized between 2017 and 2020 using either cyclophosphamide (4 g/m) plus granulocyte colony-stimulating factor (G-CSF) or G-CSF alone, with on demand plerixafor (PXF) in both groups. Although total CD34 yield was higher after chemomobilization compared with G-CSF +/- PXF (median, 13.6 × 10/kg versus 4.4 × 10/kg; P < .01), achievement of ≥2 × 10 CD34 cells (95% versus 93.7%; P = .61) and rates of mobilization failure (5% versus 6.3%; P = .61) were similar. Fewer patients required PXF with chemomobilization (12.3% versus 49.5%; P < .01), and apheresis sessions were fewer (median, 1 [range, 1 to 4] versus 2 [range, 1 to 5]). The rate of complications, including neutropenic fever, emergency department visits, and hospitalizations, was higher after chemomobilization (30% versus 7.4%; P < .01). Previous use of ≤6 cycles of lenalidomide did not impair cell yield in either group. The median cost of mobilization was 17.4% lower in the G-CSF +/- PXF group (P = .01). Between group differences in time to engraftment were not clinically significant. Given similar rates of successful mobilization, similar engraftment time, and less toxicity and lower costs compared with chemomobilization, G-CSF with on-demand PXF may be preferable in myeloma patients with adequate disease control and limited lenalidomide exposure.
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http://dx.doi.org/10.1016/j.jtct.2021.04.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8378276PMC
July 2021

Return to Work Among Young Adult Survivors of Allogeneic Hematopoietic Cell Transplantation in the United States.

Transplant Cell Ther 2021 08 22;27(8):679.e1-679.e8. Epub 2021 Apr 22.

Center for International Blood and Marrow Transplant Research), National Marrow Donor Program/Be The Match, Minneapolis, Minnesota.

Young adult (YA) survivors of allogeneic hematopoietic cell transplantation (HCT) are at risk for late psychosocial challenges, including the inability to return to work post-HCT. Work-related outcomes in this population remain understudied, however. We conducted this study to assess the post-HCT work status of survivors of allogeneic HCT who underwent HCT as YAs and to analyze the patient-, disease-, and HCT-related factors associated with their work status at 1 year post-HCT. Using Center for International Blood and Marrow Transplant Research data, we evaluated the post-HCT work status (full-time, part-time work, unemployed, or medical disability) of 1365 YA HCT survivors who underwent HCT between 2008 and 2015. Percentages of work status categories were reported at 4 time points: 6 months, 1 year, 2 years, and 3 years post-HCT. Percentages of post-HCT work status categories at the 1-year time point were also described in relation to survivors' pre-HCT work status categories. Factors associated with 1-year post-HCT work status (full-time or part-time work) were examined using logistic regression. From 6 months to 3 years post-HCT, the percentage of survivors working full-time increased from 18.3% to 50.7% and the percentage working part-time increased from 6.9% to 10.5%. Of patients in full-time work pre-HCT, 50% were unemployed or on medical disability at 1 year post-HCT. Female sex (odds ratio [OR], 0.55; 95% confidence interval [CI], 0.40 to 0.77), HCT Comorbidity Index score ≥3 (OR, 0.57; 95% CI, 0.39 to 0.82), pre-HCT unemployment (OR, 0.37; 95% CI, 0.24 to 0.56), medical disability (OR, 0.44; 95% CI, 0.28 to 0.70), development of grade III-IV acute graft-versus-host disease (OR, 0.52; 95% CI, 0.34 to 0.80), and relapse within 1 year post-HCT (OR, 0.34; 95% CI, 0.21 to 0.56) were associated with a lower likelihood of employment at 1 year post-HCT. Compared with myeloablative conditioning (MAC) with total body irradiation (TBI), MAC without TBI (OR, 1.71; 95% CI, 1.16 to 2.53) was associated with a greater likelihood of employment at 1 year post-HCT. Graduate school-level education (OR, 2.47; 95% CI, 1.49 to 4.10) was also associated with a greater likelihood of employment at 1 year post-HCT. Although the work status among YA HCT survivors continued to improve over time, a substantial subset became or remained unemployed or on medical disability. These findings underscore the need for effective interventions to support return to work in this population.
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http://dx.doi.org/10.1016/j.jtct.2021.04.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8425287PMC
August 2021

Assessment of measurable residual disease (MRD) in adult patients with acute lymphocytic leukemia: best use and a case report.

Authors:
Lori Muffly

Clin Adv Hematol Oncol 2020 Mar;18 Suppl 9(3):10-14

Blood and Marrow Transplantation, Stanford University Medical Center, Stanford, California.

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March 2020

Clinical actionability of measurable residual disease (MRD) assessment in the management of patients with hematologic malignancies: a case-based monograph.

Clin Adv Hematol Oncol 2020 Mar;18 Suppl 9(3):1-16

Blood and Marrow Transplantation, Stanford University Medical Center, Stanford, California.

New treatments for hematologic malignancies have led to outcomes that are outpacing the ability of traditional measures of response to accurately capture a patient's depth of response and risk of relapse. Assessment of measurable residual disease (MRD) offers a high-sensitivity evaluation for remaining disease present in a patient. MRD is not a surrogate marker for the detection of cancer cells, but rather a direct measure of them. MRD has quickly become an important measurement of response in patients with multiple myeloma and acute lymphocytic leukemia. Retrospective and prospective studies indicate that MRD-negative patients have better outcomes, particularly progression-free and overall survival, compared with patients who are MRD-positive. Two methods have emerged as the primary strategies for assessing MRD: next-generation sequencing (NGS) and next-generation flow (NGF). Both methods measure detectable disease in the bone marrow. The clonoSEQ® Assay, which uses NGS technology, is cleared by the US Food and Drug Administration for the detection and monitoring of MRD in bone marrow samples from patients with multiple myeloma or B-cell acute lymphoblastic leukemia. This monograph discusses the supporting research and clinical use of MRD assessment among patients with multiple myeloma and acute lymphoblastic leukemia.
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March 2020

Prospective Randomized Study of Advance Directives in Allogeneic Hematopoietic Cell Transplantation Recipients.

Transplant Cell Ther 2021 07 6;27(7):615.e1-615.e7. Epub 2021 Apr 6.

Stanford University Medical Center, Stanford, California. Electronic address:

Patients undergoing allogeneic hematopoietic cell transplantation (HCT) are at risk for high morbidity and mortality. Advance directives (AD) allow patients to express wishes regarding their care at the end of life, but these are not completed in the majority of patients undergoing HCT, with only 44% of deceased allogeneic HCT recipients at this institution completing an AD in the past decade. Increasing the AD completion rate can improve the quality of care for allogeneic HCT recipients. Our objective was to evaluate whether an alternative AD instrument can increase AD completion rate and patient satisfaction. We conducted a prospective, randomized controlled study of the traditional California AD versus a novel Letter AD, the Stanford What Matters Most Letter, in adult allogeneic HCT recipients. Patients age ≥18 years undergoing first allogeneic HCT at Stanford University were eligible. Prior to HCT conditioning, enrolled patients were assigned at random to complete either the traditional AD or the Letter AD. The primary endpoint was AD completion. The chi-square test was used to compare the AD completion rate between arms. The Wilcoxon rank-sum test was used to compare uncertainty, satisfaction with decision making, and satisfaction with the AD. Of the 212 patients who were eligible, 126 (59.4%) were enrolled and randomized. The mean age was 53.7 years, 57 (45.2%) were female, and 74 (58.7%) were non-Hispanic white. The overall AD completion rate was 71.4% and did not differ between the traditional and Letter AD arms (70.3% versus 72.6%; P = .78). Of those who completed the Letter AD, 66.7%, 42.2%, and 46.7% of patients wished to die gently/naturally, at home, and/or with hospice, respectively. In the traditional AD arm, 60.0% wished to not prolong life if recovery was unlikely. Opinion surveys did not find differences in levels of satisfaction between the traditional AD and Letter AD. Completion rates of AD on this study were high (71.4%) compared with historically reported completion rates and did not significantly differ based on AD version.
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http://dx.doi.org/10.1016/j.jtct.2021.03.030DOI Listing
July 2021

Use of Backup Stem Cells for Stem Cell Boost and Second Transplant in Patients with Multiple Myeloma Undergoing Autologous Stem Cell Transplantation.

Transplant Cell Ther 2021 05 25;27(5):405.e1-405.e6. Epub 2021 Feb 25.

Department of Medicine, Division of Blood and Marrow Transplantation and Cellular Therapy, Stanford University School of Medicine, Stanford, California.. Electronic address:

Autologous hematopoietic stem cell transplantation (ASCT) is a standard treatment for multiple myeloma (MM). Consensus guidelines recommend collecting sufficient stem cells in case there is a need for stem cell boost for delayed/poor engraftment or for future second ASCT. However, collecting and storing backup stem cells in all patients requires significant resources and cost, and the rates of backup stem cell utilization are not well studied. We sought to examine the utilization of backup stem cells (BSCs) in patients with MM undergoing ASCT. Patients with MM aged ≥18 years old who underwent first ASCT at our institution from January 2010 through December 2015 and collected sufficient stem cells for at least 2 transplants were included in this single-center retrospective study. This timeframe was selected to allow for adequate follow-up. A total of 393 patients were included. The median age was 58 years (range, 25-73). After a median follow-up of 6 years, the median progression-free survival (PFS) of the cohort was 3 years. Sixty-one percent (n = 240) of patients progressed or relapsed. Chemotherapy-based mobilization was used in almost all patients (98%). The median total CD34+ cells collected was 18.2 × 10/kg (range, 3.4-112.4). A median of 5.7 × 10 CD34+ cells/kg (range, 1.8-41.9) was infused during the first ASCT, and a median of 10.1 × 10 CD34+ cells/kg (range, 1.5-104.5) was cryopreserved for future use. Of the patients, 6.9% (n = 27) used backup stem cells, with 2.3% (n = 10) using them for stem cell boost, 4.6% (n = 18) for a second salvage ASCT, including 1 patient for both stem cell boost and second ASCT. Rates of backup stem cell use among patients aged <60, 60-69, and ≥70 years were 7.8%, 5.7%, and 5.9%, respectively. There was a trend toward higher rates of backup stem cell use for second ASCT in patients who were younger, had suboptimal disease control at time of first ASCT, and longer PFS. The median dose of stem cell boost given was 5.6 × 10 CD34+ cells/kg (range, 1.9-20). The median time from stem cell boost to neutrophil, hemoglobin, and platelet engraftment was 4 (range, 2-11), 15 (range, 4-34), and 12 (range, 0-34) days, respectively. Lower CD34+ dose and older age at time of ASCT predicted need for stem cell boost. With new salvage therapies for relapsed MM, the rates of second ASCT are very low. The low rates of use suggest that institutional policies regarding universal BSC collection and long-term storage should be reassessed and individualized. However, need for stem cell boost in 2.3% of patients may present a challenge to that.
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http://dx.doi.org/10.1016/j.jtct.2021.02.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8113075PMC
May 2021

Immune reconstitution and infectious complications following axicabtagene ciloleucel therapy for large B-cell lymphoma.

Blood Adv 2021 01;5(1):143-155

Division of Blood and Marrow Transplantation, Department of Medicine, Stanford University School of Medicine, Stanford, CA.

Chimeric antigen receptor (CAR) T-cell therapy targeting CD19 has significantly improved outcomes in the treatment of refractory or relapsed large B-cell lymphoma (LBCL). We evaluated the long-term course of hematologic recovery, immune reconstitution, and infectious complications in 41 patients with LBCL treated with axicabtagene ciloleucel (axi-cel) at a single center. Grade 3+ cytopenias occurred in 97.6% of patients within the first 28 days postinfusion, with most resolved by 6 months. Overall, 63.4% of patients received a red blood cell transfusion, 34.1% of patients received a platelet transfusion, 36.6% of patients received IV immunoglobulin, and 51.2% of patients received growth factor (granulocyte colony-stimulating factor) injections beyond the first 28 days postinfusion. Only 40% of patients had recovered detectable CD19+ B cells by 1 year, and 50% of patients had a CD4+ T-cell count <200 cells per μL by 18 months postinfusion. Patients with durable responses to axi-cel had significantly longer durations of B-cell aplasia, and this duration correlated strongly with the recovery of CD4+ T-cell counts. There were significantly more infections within the first 28 days compared with any other period of follow-up, with the majority being mild-moderate in severity. Receipt of corticosteroids was the only factor that predicted risk of infection in a multivariate analysis (hazard ratio, 3.69; 95% confidence interval, 1.18-16.5). Opportunistic infections due to Pneumocystis jirovecii and varicella-zoster virus occurred up to 18 months postinfusion in patients who prematurely discontinued prophylaxis. These results support the use of comprehensive supportive care, including long-term monitoring and antimicrobial prophylaxis, beyond 12 months after axi-cel treatment.
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http://dx.doi.org/10.1182/bloodadvances.2020002732DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7805341PMC
January 2021

CD22-directed CAR T-cell therapy induces complete remissions in CD19-directed CAR-refractory large B-cell lymphoma.

Blood 2021 Apr;137(17):2321-2325

Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University, Stanford, CA.

The prognosis of patients with large B-cell lymphoma (LBCL) that progresses after treatment with chimeric antigen receptor (CAR) T-cell therapy targeting CD19 (CAR19) is poor. We report on the first 3 consecutive patients with autologous CAR19-refractory LBCL who were treated with a single infusion of autologous 1 × 106 CAR+ T cells per kilogram targeting CD22 (CAR22) as part of a phase 1 dose-escalation study. CAR22 therapy was relatively well tolerated, without any observed nonhematologic adverse events higher than grade 2. After infusion, all 3 patients achieved complete remission, with all responses continuing at the time of last follow-up (mean, 7.8 months; range, 6-9.3). Circulating CAR22 cells demonstrated robust expansion (peak range, 85.4-350 cells per microliter), and persisted beyond 3 months in all patients with continued radiographic responses and corresponding decreases in circulating tumor DNA beyond 6 months after infusion. Further accrual at a higher dose level in this phase 1 dose-escalation study is ongoing and will explore the role of this therapy in patients in whom prior CAR T-cell therapies have failed. This trial is registered on clinicaltrials.gov as #NCT04088890.
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http://dx.doi.org/10.1182/blood.2020009432DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8085484PMC
April 2021

Routine use of gemtuzumab ozogamicin in 7 + 3-based inductions for all 'non-adverse' risk AML.

Leuk Lymphoma 2021 06 24;62(6):1510-1513. Epub 2021 Jan 24.

Division of Hematology, Stanford Cancer Institute, Stanford University, Stanford, CA, USA.

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http://dx.doi.org/10.1080/10428194.2021.1876869DOI Listing
June 2021

Philadelphia chromosome positive acute lymphoblastic leukemia in adults: Therapeutic options and dilemmas in 2020.

Semin Hematol 2020 07 11;57(3):137-141. Epub 2020 Sep 11.

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

The incorporation of tyrosine kinase inhibitors (TKI) into front-line therapy for adults with Philadelphia chromosome positive acute lymphoblastic leukemia has dramatically altered response rates and significantly improved outcomes, such that this entity may no longer be considered a high risk acute lymphoblastic leukemia subgroup. In this review article, we summarize approaches to front-line therapy in the TKI era, including intensive chemotherapy-based regimens and deintensified therapy. We also review optimal disease monitoring strategies, discuss the role of consolidative hematopoietic cell transplantation, and touch on options for relapsed disease. The incorporation of novel targeted agents in conjunction with TKIs into front-line therapy will likely alter the future therapeutic approaches to this disease.
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http://dx.doi.org/10.1053/j.seminhematol.2020.09.002DOI Listing
July 2020

Hepatic veno-occlusive disease in allogeneic stem cell transplant recipients with prior exposure to gemtuzumab ozogamicin or inotuzumab ozogamicin.

Leuk Lymphoma 2021 02 29;62(2):257-263. Epub 2020 Sep 29.

Division of Blood and Marrow Transplantation, Stanford University, Stanford, CA, USA.

Hepatic veno-occlusive disease (VOD/sinusoidal obstructive syndrome) represents a constellation of clinical findings including right upper quadrant pain, jaundice, hepatomegaly, and ascites. In the post-hematopoietic stem cell transplant (SCT) setting, the reported incidence has been 10-15%, with severe VOD historically resulting in high mortality rates. Novel agents including calicheamicin conjugated with CD33 (gemtuzumab ozogamicin; GO) and CD22 (inotuzumab ozogamicin; InO) are increasingly used for the treatment of acute myeloid leukemia and acute lymphoblastic leukemia, respectively. Both GO and InO are highly active, but also have unique hepatotoxicity profiles, including a higher risk of VOD in recipients of SCT. Introduction of GO and InO into pre-SCT leukemia management adds additional complexity to SCT patient selection and toxicity monitoring. In this article, we describe and review the risks and management associated with VOD in SCT recipients exposed to GO and InO.
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http://dx.doi.org/10.1080/10428194.2020.1827247DOI Listing
February 2021

Outcomes with Autologous or Allogeneic Stem Cell Transplantation in Patients with Plasma Cell Leukemia in the Era of Novel Agents.

Biol Blood Marrow Transplant 2020 12 19;26(12):e328-e332. Epub 2020 Sep 19.

Stanford Cancer Institute, Stanford University Medical Center, Stanford, California. Electronic address:

Plasma cell leukemia (PCL) is a rare and very aggressive plasma cell disorder. The optimal treatment approach, including whether to pursue an autologous (auto) or allogeneic (allo) stem cell transplantation (SCT) is not clear, given the lack of clinical trial-based evidence. This single-center retrospective study describes the outcomes of 16 patients with PCL (n = 14 with primary PCL) who underwent either autoSCT (n = 9) or alloSCT (n = 7) for PCL in the era of novel agents, between 2007 and 2019. The median age of the cohort was 58 years. High-risk cytogenetics were found in 50% of the patients. All patients received a proteasome inhibitor and/or immunomodulatory drug-based regimen before transplantation. At the time of transplantation, 10 patients (62%) obtained at least a very good partial response (VGPR). The response after autoSCT (3 months) was at least a VGPR in 6 patients (67%; complete response [CR] in 5). All patients undergoing alloSCT achieved a CR at 3 months. Maintenance therapy was provided to 5 patients (56%) after autoSCT. The median progression-free survival after transplantation was 6 months in the autoSCT group, compared with 18 months in the alloSCT group (P = .09), and median overall survival (OS) after transplantation in the 2 groups was 19 months and 40 months, respectively (P = .41). The median OS from diagnosis was 27 months and 49 months, respectively (P = .50). Of the 11 deaths, 10 patients (91%) died of relapsed disease. AlloSCT was not observed to offer any significant survival advantage over autoSCT in PCL, in agreement with recent reports, and relapse remains the primary cause of death in these patients.
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http://dx.doi.org/10.1016/j.bbmt.2020.08.035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8083942PMC
December 2020

Nonmyeloablative allogeneic transplantation achieves clinical and molecular remission in cutaneous T-cell lymphoma.

Blood Adv 2020 09;4(18):4474-4482

Department of Dermatology.

The majority of patients with refractory, advanced-stage mycosis fungoides (MF) or Sézary syndrome (SS) have a life expectancy of <5 years. Here, we report a phase 2 study of a novel nonmyeloablative allogeneic transplantation strategy tailored for this patient population. This study has completed the enrollment, and 35 patients (13 MF, 22 SS) have undergone transplant as planned. The majority (80%) of the patients had stage IV disease and received multiple previous systemic therapies. All patients had active disease at the time of conditioning using total skin electron beam therapy, total lymphoid irradiation, and antithymocyte globulin, and received allograft infusion as outpatients. Cyclosporine or tacrolimus and mycophenolate mofetil were used for graft-versus-host disease (GVHD) prophylaxis. Patients tolerated the transplant well, with 1- and 2-year nonrelapse mortality of 3% and 14%, respectively. The day +180 cumulative incidence of grade 2 to 4 acute GVHD was 16%, and the 2-year incidence of moderate/severe chronic GVHD was 32%. With a median posttransplant follow-up of 5.4 years, the 2-, 3-, and 5-year overall survival rates were 68%, 62%, and 56%. Using high-throughput sequencing of the T-cell receptor for minimal residual disease monitoring, we observed that 43% achieved molecular remission, which was associated with a lower incidence of disease progression or relapse (9% vs 87%; P = .02). Our study also showed that patients who were aged ≥65 years at the time of allotransplant had similar clinical outcomes compared with younger patients. Thus, we have developed an alternative and potentially curative nonmyeloablative allogeneic transplant regimen for patients with advanced stage MF/SS. This trial was registered at www.clinicaltrials.gov as #NCT00896493.
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http://dx.doi.org/10.1182/bloodadvances.2020001627DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7509879PMC
September 2020

How I Approach the Patient Who Has MRD or Relapse After Transplant.

Authors:
Lori Muffly

Clin Lymphoma Myeloma Leuk 2020 09;20 Suppl 1:S32-S33

Stanford University, 300 Pasteur Drive, Stanford, CA 94305, USA. Electronic address:

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http://dx.doi.org/10.1016/S2152-2650(20)30453-5DOI Listing
September 2020

Outcomes with autologous stem cell transplant vs. non-transplant therapy in patients 70 years and older with multiple myeloma.

Bone Marrow Transplant 2021 02 11;56(2):368-375. Epub 2020 Aug 11.

Stanford Cancer Institute, Stanford University Medical Center, Stanford, CA, USA.

We evaluated 79 patients with multiple myeloma (MM) ≥70 years referred to our blood and marrow transplant clinic, within 1 year of diagnosis from 2010 to 2019, for consideration of autologous stem cell transplant (ASCT). Thirty-eight (48%) of 79 patients underwent ASCT. ASCT was not pursued in 41 (52%) patients due to: patient or physician preference in 80% (n = 33) or ineligibility in 20% (n = 8). Baseline characteristics of patients in the two groups were similar. Median PFS from treatment start amongst patients undergoing ASCT (n = 38) vs. not (n = 41) was 41 months vs. 33 months, p = 0.03. There was no difference in OS, with estimated 5-year OS of 73% vs. 83%, respectively (p = 0.86). Day +100 transplant-related mortality (TRM) was 0%. ASCT was an independent favorable prognostic factor for PFS in multivariate analysis, after accounting for HCT-CI score, performance status, hematologic response, and maintenance. Finally, patients ≥70 years undergoing ASCT had similar PFS compared to a contemporaneous institutional cohort of patients <70 years (n = 631) (median PFS from transplant: 36 vs. 47 months, p = 0.25). In this retrospective analysis, ASCT was associated with low TRM and better PFS in fit older adults with MM compared to non-transplant therapy, with comparable benefits as seen in younger patients.
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http://dx.doi.org/10.1038/s41409-020-01026-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8019397PMC
February 2021

Late Effects in Survivors of Adolescent and Young Adult Acute Lymphoblastic Leukemia.

JNCI Cancer Spectr 2020 Aug 2;4(4):pkaa025. Epub 2020 Apr 2.

Division of Hematology and Oncology, Center for Oncology Hematology Outcomes Research and Training (COHORT), University of California, Davis School of Medicine, Sacramento, CA, USA.

Background: Knowledge regarding late effects (medical conditions and subsequent neoplasms) in survivors of adolescent and young adult (AYA) acute lymphoblastic leukemia (ALL) is lacking.

Methods: Using the population-based California Cancer Registry linked with California hospitalization data, we evaluated late effects in 1069 AYAs (aged 15-39 years) diagnosed with ALL in California between 1995 and 2012 and surviving a minimum of 3 years from diagnosis.

Results: The estimated 10-year cumulative incidence of subsequent endocrine disease (28.7%, 95% confidence interval [CI] = 25.8% to 31.6%) and cardiac disease (17.0%, 95% CI = 14.6% to 19.5%) were strikingly high; avascular necrosis (9.6%, 95% CI = 7.8% to 11.6%), liver disease (6.5%, 95% CI = 5.0% to 8.3%), respiratory disease (6.2%, 95% CI = 4.8% to 8.0%), seizure and/or stroke (4.3%, 95% CI = 3.1% to 5.8%), renal disease (3.1%, 95% CI = 2.1% to 4.4%), and second neoplasms (1.4%, 95% CI = 0.7% to 2.4%) were estimated to occur at 10 years with the reported frequencies. Multivariable analyses including the entire patient cohort demonstrated that public or no insurance (vs private and/or military insurance) and receipt of hematopoietic cell transplantation were independently associated with the occurrence of all late effects considered. In multivariable analyses limited to the 766 AYAs who were not transplanted, we continued to find a statistically significant association between public and no insurance and the occurrence of all late effects. Frontline regimen type (pediatric vs adult) was not statistically significantly associated with any of the late effect categories.

Conclusions: This large population-based analysis is among the first to describe late effects in survivors of AYA ALL. The strong association between insurance type and late effects suggests that AYAs with public or no insurance may have reduced access to survivorship care following completion of ALL therapy.
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http://dx.doi.org/10.1093/jncics/pkaa025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7368465PMC
August 2020

Treatment Complications and Survival Among Children and Young Adults With Acute Lymphoblastic Leukemia.

JCO Oncol Pract 2020 10 11;16(10):e1120-e1133. Epub 2020 Jun 11.

Division of Health Policy and Management, Department of Public Health Sciences, University of California Davis School of Medicine, Sacramento, CA.

Purpose: We previously demonstrated lower early mortality for young adults (YAs) with acute lymphoblastic leukemia (ALL) who received induction treatment at specialized cancer centers (SCCs) versus community hospitals. The aim of this study is to determine the impact of inpatient location of treatment throughout therapy on long-term survival, complications, and cost-associations that have not yet been evaluated at the population level.

Methods: Using the California Cancer Registry linked to a hospitalization database, we identified patients, 0-39 years of age, diagnosed with first primary ALL who received inpatient treatment between 1991 and 2014. Patients were classified as receiving all or part or none of their inpatient treatment at an SCC within 3 years of diagnosis. Inverse probability-weighted, multivariable Cox regression models estimated the associations between location of treatment and sociodemographic and clinical factors with survival. We compared 3-year inpatient costs overall and per day by age group and location of care.

Results: Eighty-four percent (0-18 years; n = 4,549) of children and 36% of YAs (19-39 years; n = 683) received all treatment at SCCs. Receiving all treatment at an SCC was associated with superior leukemia-specific (hazard ratio [HR], 0.76; 95% CI, 0.67 to 0.88) and overall survival (HR, 0.87; 95% CI, 0.77 to 0.97) in children and in YAs (HR, 0.71; 95% CI, 0.61 to 0.83; HR, 0.70; 95% CI, 0.62 to 0.80) even after controlling for complications. The cost of inpatient care during the full course of therapy was higher in patients receiving all of their care at SCCs.

Conclusion: Our results demonstrate that inpatient treatment at an SCC throughout therapy is associated with superior survival; therefore, strong consideration should be given to referring these patients to SCCs.
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http://dx.doi.org/10.1200/JOP.19.00572DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8189609PMC
October 2020

Calcineurin-inhibitor induced pain syndrome after stem cell transplant.

Leuk Lymphoma 2020 09 20;61(9):2230-2233. Epub 2020 May 20.

Division of Blood and Marrow Transplantation, Stanford University Medical Center, Stanford, CA, USA.

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http://dx.doi.org/10.1080/10428194.2020.1765235DOI Listing
September 2020

Hematopoietic Cell Transplantation for Philadelphia Chromosome Negative Adult Acute Lymphoblastic Leukemia in the Modern Era of Immune Therapy.

Curr Hematol Malig Rep 2020 06;15(3):187-193

Division of Blood and Marrow Transplantation, Stanford University, 300 Pasteur Drive H0144, Stanford, CA, 94305, USA.

Purpose Of Review: This review will discuss the data and controversies related to HCT in the front-line and relapsed/refractory setting in the context of newly available targeted immunotherapies.

Recent Findings: Recent studies in adult Ph-negative ALL support the use of measurable residual disease (MRD) response to front-line therapy to guide consolidation. As such, most MRD-negative patients do not require front-line HCT. Blinatumomab benefits patients with B-ALL with MRD+ complete response (CR) and can be used as a bridge to HCT; whether HCT is still required in this setting is an area of ongoing inquiry. Blinatumomab and inotuzumab result in high rates of MRD negative CR in adults with relapsed/refractory ALL and allow more patients with relapsed disease to receive HCT. Chimeric antigen receptor T cell (CAR-T) therapies may serve as a bridge to HCT or as a stand-alone therapy for relapsed/refractory patients; data suggests there may be greater benefit to consolidating CAR-T with HCT in HCT-naïve adults. The decision to incorporate consolidative allogeneic HCT into front-line therapy should be primarily guided by MRD status and the ALL regimen utilized. Targeted immunotherapies result in high MRD-negative CR rates, allowing more adults with relapsed/refractory ALL to be successfully bridged to HCT; early incorporation of these therapies may also prove valuable in reducing the need for HCT in the front-line setting by increasing MRD negative CR rates.
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http://dx.doi.org/10.1007/s11899-020-00579-0DOI Listing
June 2020
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