Publications by authors named "Karen K Ballen"

112 Publications

Guidelines for Adult Patient Selection and Conditioning Regimens in Cord Blood Transplant Recipients with Hematologic Malignancies and Aplastic Anemia.

Transplant Cell Ther 2021 Apr;27(4):286-291

Blood and Marrow Transplant Program, University of Minnesota, Minneapolis, Minnesota.

For cord blood transplantation (CBT), appropriate patient and conditioning regimen selection is necessary to achieve long-term disease-free survival. This review aims to provide comprehensive guidelines on these issues using evidence from the literature and experience at dedicated CBT centers. Topics include patient and disease characteristics that make CBT a good or poor choice and a review of outcomes in commonly used conditioning regimens in CBT. This is accompanied with recommendations on regimen intensity based on disease, organ function, and patient performance status and age. In addition, the use of antithymocyte globulin in CBT is discussed, as is the choice of conditioning in aplastic anemia patients who have access to acceptable CB units.
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http://dx.doi.org/10.1016/j.jtct.2020.11.008DOI Listing
April 2021

Worldwide Network for Blood and Marrow Transplantation (WBMT) Recommendations Regarding Essential Medications Required To Establish An Early Stage Hematopoietic Cell Transplantation Program.

Transplant Cell Ther 2021 Mar 16;27(3):267.e1-267.e5. Epub 2020 Dec 16.

Oncology Center, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia; Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota.

Establishing a hematopoietic cell transplantation (HCT) program is complex. Planning is essential while establishing such a program to overcome the expected challenges. Authorities involved in HCT program establishment will need to coordinate the efforts between the different departments required to start up the program. One essential department is pharmacy and the medications required. To help facilitate this, the Worldwide Network for Blood and Marrow Transplantation organized a structured survey to address the essential medications required to start up an HCT program. A group of senior physicians and pharmacists prepared a list of the medications used at the different phases of transplantation. These drugs were then rated by a questionnaire using a scale of necessity based on the stage of development of the transplant program. The questionnaire was sent to 30 physicians, in different parts of the world, who have between 5 and 40 years of experience in autologous and/or allogeneic transplantation. This group of experts scored each medication on a 7-point scale, ranging from an absolute requirement (score of 1) to not required (score of 7). The results are presented here to help guide the prioritization of required medications.
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http://dx.doi.org/10.1016/j.jtct.2020.12.015DOI Listing
March 2021

Epidemiology of acute myeloid leukemia in Virginia: Excellent survival outcomes for patients in rural Appalachia.

Cancer Rep (Hoboken) 2021 Mar 9:e1354. Epub 2021 Mar 9.

Division of Hematology/Oncology, University of Virginia Health System, Charlottesville, Virginia, USA.

Background: Acute myeloid leukemia, the most common acute leukemia in adults, has a poor overall survival. Studies have suggested that certain socioeconomic factors such as living in a rural or farming area are associated with worse outcomes. Since 42% of acute myeloid leukemia patients seen in our academic center reside in a rural area, we have a unique opportunity to study outcomes of patients in rural versus urban settings.

Aim: This analysis evaluates the effect of geography and socioeconomic factors on the biology, treatment, and overall survival of patients with acute myeloid leukemia, with the goal of understanding health care disparities.

Methods And Results: Patient characteristics, cytogenetic data, treatment history, and overall survival were collected and analyzed to identify differences between urban and rural residency. This cohort included 42% of patients who resided in a rural area at the time of acute myeloid leukemia diagnosis. There was no difference in overall survival between the cohorts. The 1 year overall survival for the entire cohort was 47.9%. There was no difference detected in rates of adverse cytogenetics between the rural and urban cohorts. Similar numbers of patients received induction chemotherapy or proceeded to allogeneic stem cell transplant between the cohorts.

Conclusions: This study highlights that similar outcomes can be achieved in rural and urban patients, suggesting that intensive efforts at telehealth, education, and collaboration with local oncology practices may be beneficial.
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http://dx.doi.org/10.1002/cnr2.1354DOI Listing
March 2021

Umbilical cord blood: The promise and the uncertainty.

Stem Cells Transl Med 2020 10 3;9(10):1153-1162. Epub 2020 Jul 3.

Division of Hematology/Oncology, University of Virginia, Charlottesville, Virginia, USA.

Unfortunately, many patients referred for hematopoietic cell transplant will not have a fully matched related donor, and finding matched unrelated donors through the registry may be difficult, especially if the recipient is not of Northern European descent [N Engl J Med 2014;371:339-348]. Umbilical cord blood (UCB) has been an available graft source for hematopoietic cell transplant for more than 30 years, since the first UCB transplant was performed in the late 1980s [N Engl J Med 1989;321:1174-1178]. UCB is readily available, has low immunogenicity, and does not require as strict of human leukocyte antigen (HLA) matching compared to other graft sources [N Engl J Med 2004;351:2265-2275]. According to data from the Center for International Blood and Marrow Transplant Research (CIBMTR), an estimated 500 patients in the US will have received a UCB transplant in 2018. Since 2014, haploidentical transplants have surpassed UCB transplants performed in the United States (CIBMTR Summary Slides, 2018, available at https://www.cibmtr.org). Increased use of haploidentical transplants has brought to light concerns about UCB transplants, including delayed engraftment and graft failure, increased nonrelapse mortality, increased infection risk, and UCB acquisition costs [Lancet Oncol 2010;11:653-660; Biol Blood Marrow Transplant 2019;1456-1464]. These concerns will need to be addressed for UCB to remain a viable option as a graft source for hematopoietic cell transplant. Other promising therapeutic benefits for UCB, in addition to hematopoietic cell transplant, is its use in regenerative medicine and immune modulation, which is currently being evaluated in ongoing clinical trials.
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http://dx.doi.org/10.1002/sctm.19-0288DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7519764PMC
October 2020

Allogeneic Transplantation for Myelofibrosis with Novel Graft-versus-Host Disease Prophylaxis.

Acta Haematol 2021 22;144(2):124-125. Epub 2020 Jun 22.

Division of Hematology/Oncology, University of Virginia Cancer Center, Charlottesville, Virginia, USA.

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http://dx.doi.org/10.1159/000508198DOI Listing
March 2021

MLL-Rearranged Acute Lymphoblastic Leukemia.

Curr Hematol Malig Rep 2020 04;15(2):83-89

Department of Medicine, Division of Hematology and Oncology, University of Virginia School of Medicine, 1215 Lee Street, Charlottesville, VA, 22903, USA.

Purpose Of Review: Rearrangements of the histone lysine [K]-MethylTransferase 2A gene (KMT2A) gene on chromosome 11q23, formerly known as the mixed-lineage leukemia (MLL) gene, are found in 10% and 5% of adult and children ALL cases, respectively. The most common translocated genes are AFF1 (formerly AF4), MLLT3 (formerly AF9), and MLLT1 (formerly ENL). The bimodal incidence of MLL-r-ALL usually peaks in infants in their first 2 years of life and then declines thereafter during the pediatric/young adult phase until it increases again with age. MLL-rearranged ALL (MLL-r-ALL) is characterized by hyperleukocytosis, aggressive behavior with early relapse, relatively high incidence of central nervous system (CNS) involvement, and poor prognosis.

Recent Findings: MLL-r-ALL cells are characterized by relative resistance to corticosteroids (due to Src kinase-induced phosphorylation of annexin A2) and L-asparaginase therapy, but they are sensitive to cytarabine chemotherapy (due to increased levels of hENT1 expression). Potential therapeutic targets include FLT3 inhibitors, MEK inhibitors, HDAC inhibitors, BCL-2 inhibitors, MCL-1 inhibitors, proteasome inhibitors, hypomethylating agents, Dot1L inhibitors, and CDK inhibitors. In this review, we discuss MLL-r-ALL focusing on clinical presentation, risk stratification, drug resistance, and treatment strategies, including potential novel therapeutic targets.
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http://dx.doi.org/10.1007/s11899-020-00582-5DOI Listing
April 2020

A phase 1 study of the antibody-drug conjugate brentuximab vedotin with re-induction chemotherapy in patients with CD30-expressing relapsed/refractory acute myeloid leukemia.

Cancer 2020 03 20;126(6):1264-1273. Epub 2019 Dec 20.

Division of Hematology/Oncology, University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, Maryland.

Background: Outcomes for patients with relapsed/refractory acute myeloid leukemia (R/R AML) remain poor. Novel therapies specifically targeting AML are of high interest. Brentuximab vedotin (BV) is an antibody-drug conjugate that is specific for human CD30. In this phase 1 dose escalation study, the authors evaluated the safety of BV combined with mitoxantrone, etoposide, and cytarabine (MEC) re-induction chemotherapy for patients with CD30-expressing R/R AML.

Methods: Using a standard dose escalation design, the authors evaluated 3 dose levels of BV (0.9 mg/kg, 1.2 mg/kg, and 1.8 mg/kg) administered once on day 1 followed by MEC on days 3 through 7.

Results: There were no dose-limiting toxicities noted and the maximum tolerated dose was not reached. The recommended phase 2 dose of BV was determined to be 1.8 mg/kg when combined with MEC. The side effect profile was similar to that expected from MEC chemotherapy alone, with the most common grade ≥3 toxicities being febrile neutropenia, thrombocytopenia, and anemia (toxicities were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.0]). Among the 22 patients enrolled on the trial, the composite response rate was 36%, with a composite response rate of 42% noted among those who received the highest dose of BV. The median overall survival was 9.5 months, with a median disease-free survival of 6.8 months observed among responders. Approximately 55% of patients were able to proceed with either allogeneic hematopoietic stem cell transplantation or donor lymphocyte infusion.

Conclusions: The combination of BV with MEC was found to be safe in patients with CD30-expressing R/R AML and warrants further study comparing this combination with the use of MEC alone in this population (ClinicalTrials.gov identifier NCT01830777).

Lay Summary: The outcomes for patients with relapsed/refractory acute myeloid leukemia (R/R AML) are exceptionally poor. New and emerging treatment combinations are actively being studied in an effort to improve outcomes. The authors examined the combination of brentuximab vedotin, an antibody product that recognizes a marker called CD30, with mitoxantrone, etoposide, and cytarabine (MEC), a common chemotherapy regimen, in patients with R/R AML that expressed the CD30 marker. The authors found that the combination was safe and well tolerated. Future studies comparing this new combination with the use of MEC alone can help to inform its effectiveness for this patient population.
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http://dx.doi.org/10.1002/cncr.32657DOI Listing
March 2020

Alisertib plus induction chemotherapy in previously untreated patients with high-risk, acute myeloid leukaemia: a single-arm, phase 2 trial.

Lancet Haematol 2020 Feb 11;7(2):e122-e133. Epub 2019 Dec 11.

Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.

Background: Increased aurora A kinase (AAK) expression occurs in acute myeloid leukaemia; AAK inhibition is a promising therapeutic target in this disease. We therefore aimed to assess the activity of alisertib combined with 7 + 3 induction chemotherapy in previously untreated patients with high-risk acute myeloid leukaemia.

Methods: We did a single-arm, phase 2 trial of patients recruited from the Dana-Farber/Harvard Cancer Center in the USA. Eligible patients had previously untreated acute myeloid leukaemia, an Eastern Cooperative Oncology Group performance status of 0-2, and were at high risk of disease as defined by the presence of an adverse-risk karyotype, the presence of secondary acute myeloid leukaemia arising from previous myelodysplastic syndrome or myeloproliferative neoplasm, the presence of therapy-related acute myeloid leukaemia, or being 65 years or older. Enrolled patients received 7 + 3 induction chemotherapy of continuous infusion of cytarabine (100 mg/m per day on days 1-7) and intravenous bolus of idarubicin (12 mg/m per day on days 1-3). Oral alisertib (30 mg) was given twice per day on days 8-15. Patients could receive up to four consolidation cycles with cytarabine and alisertib, and alisertib maintenance for 12 months. The primary endpoint was a composite including the proportion of patients achieving complete remission and those with a complete remission with incomplete neutrophil or platelet count recovery. Analyses were per-protocol. This study is registered with Clinicaltrials.gov, number NCT02560025, and has completed enrolment.

Findings: Between Dec 31, 2015, and Aug 1, 2017, we enrolled a total of 39 eligible patients. 19 (49%) of 39 patients had secondary acute myeloid leukaemia and three (8%) had therapy-related acute myeloid leukaemia. At mid-induction, 33 (85%) of 39 patients showed marrow aplasia, six (15%) received re-induction. The median follow-up was 13·7 months (IQR 12·7-14·4). Composite remission was 64% (two-stage 95% CI 48-79), with 20 (51%) of 39 patients achieving complete remission and five (13%) achieving complete remission with incomplete neutrophil or platelet count recovery. The most common grade 3 or 4 adverse events included febrile neutropenia (16 [41%] of 39), neutropenia (12 [31%]), thrombocytopenia (13 [33%]), anaemia (11 [28%]), anorexia (nine [23%]), and oral mucositis (four [10%]). No treatment-related deaths were observed.

Interpretation: These results suggest that alisertib combined with induction chemotherapy is active and safe in previously untreated patients with high-risk acute myeloid leukaemia. This study met criteria to move forward to a future randomised trial.

Funding: Millennium Pharmaceuticals.
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http://dx.doi.org/10.1016/S2352-3026(19)30203-0DOI Listing
February 2020

What have we learned from transplanting older patients?

Best Pract Res Clin Haematol 2019 12 18;32(4):101110. Epub 2019 Oct 18.

University of Virginia Cancer Center, 1300 Jefferson Park Avenue, Charlottesville, VA, 22908, USA. Electronic address:

Aggressive curative therapies have now been extended to patients older than 65 years, a fast-growing segment of the population. As the number of allogeneic transplants in patients older than age 65 is increasing, attention is now focused on improving outcomes in this group. This paper discusses important aspects of allogeneic transplant in the older patient, focusing on donor and patient selection, choice of conditioning regimen and graft source, and the importance of timely access to a transplant center.
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http://dx.doi.org/10.1016/j.beha.2019.101110DOI Listing
December 2019

Treatment of acute leukaemia in adult Jehovah's Witnesses.

Br J Haematol 2020 09 6;190(5):696-707. Epub 2019 Nov 6.

Department of Medicine, Division of Hematology and Oncology, University of Virginia School of Medicine, Charlottesville, VA, USA.

Since Jehovah's Witness (JW) patients diagnosed with leukaemia refuse blood transfusions, they are often denied intensive chemotherapy for fear they could not survive myeloablation without blood transfusion support. Treatment of JW patients with acute leukaemia is challenging and carries a higher morbidity and mortality; however, the refusal of blood products should not be an absolute contraindication to offer multiple treatment modalities including haematopoietic stem cell transplantation. In this review we discuss their optimal management and describe alternative modalities to blood transfusions to provide sufficient oxygenation and prevent bleeding.
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http://dx.doi.org/10.1111/bjh.16284DOI Listing
September 2020

A phase II study of reduced intensity double umbilical cord blood transplantation using fludarabine, melphalan, and low dose total body irradiation.

Bone Marrow Transplant 2020 04 15;55(4):804-810. Epub 2019 Oct 15.

Division of Hematologic Malignancies, Dana-Farber Cancer Institute, Boston, MA, USA.

In this multicenter Phase 2 single arm study, we substituted low dose total body irradiation (TBI) for antithymocyte globulin (ATG) in a reduced intensity conditioning regimen with the intent to lower the risk for viral infections after double umbilical cord blood (UCB) transplantation. The conditioning regimen consisted of fludarabine (30 mg/m/day, Day -7 to -2), melphalan (100 mg/m/day, Day -1), and TBI (200cGy, Day 0). Graft-versus-host disease prophylaxis was sirolimus and tacrolimus. Thirty-one patients were treated on the protocol. The median time of follow-up for survivors was 24 months (range, 3.3-55.1). Nineteen patients experienced a total of 24 clinically significant viral reactivations or infections, with 1-year cumulative incidence rate of first significant viral event as 64% (95% CI, 43-79%), compared with our historical control of 53%. Within the context of these 24 clinically significant viral reactivations, there were a total of 10 infections with organ involvement. Nonrelapse mortality was 28% (95% CI 13-45%) at 2 years. The 2-year overall and progression-free survivals were 53% (95% CI 33-69%) and 47% (95% CI 28-64%), respectively. In conclusion, the substitution of low dose TBI for ATG did not decrease the incidence of significant viral events after UCB transplantation.
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http://dx.doi.org/10.1038/s41409-019-0715-xDOI Listing
April 2020

Myeloablative vs reduced intensity T-cell-replete haploidentical transplantation for hematologic malignancy.

Blood Adv 2019 10;3(19):2836-2844

Center for International Blood and Marrow Transplant Research, and.

In the absence of prospective studies that examine the effect of conditioning regimen intensity after T-cell-replete haploidentical transplant for acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and myelodysplastic syndrome (MDS), a retrospective cohort analysis was performed. Of the 1325 eligible patients (AML, n = 818; ALL, n = 286; and MDS, n = 221), 526 patients received a myeloablative regimen and 799 received a reduced-intensity regimen. Graft-versus-host disease prophylaxis was uniform with posttransplant cyclophosphamide, a calcineurin inhibitor, and mycophenolate mofetil. The primary end point was disease-free survival. Cox regression models were built to study the effect of conditioning regimen intensity on transplant outcomes. For patients aged 18 to 54 years, disease-free survival was lower (hazard ratio [HR], 1.34; 42% vs 51%; = .007) and relapse was higher (HR, 1.51; 44% vs 33%; = .001) with a reduced-intensity regimen compared with a myeloablative regimen. Nonrelapse mortality did not differ according to regimen intensity. For patients aged 55 to 70 years, disease-free survival (HR, 0.97; 37% vs 43%; = .83) and relapse (HR, 1.32; 42% vs 31%; = .11) did not differ according to regimen intensity. Nonrelapse mortality was lower with reduced-intensity regimens (HR, 0.64; 20% vs 31%; = .02). Myeloablative regimens are preferred for AML, ALL, and MDS; reduced-intensity regimens should be reserved for those unable to tolerate myeloablation.
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http://dx.doi.org/10.1182/bloodadvances.2019000627DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6784523PMC
October 2019

Worldwide Network for Blood and Marrow Transplantation (WBMT) perspective: the role of biosimilars in hematopoietic cell transplant: current opportunities and challenges in low- and lower-middle income countries.

Bone Marrow Transplant 2020 04 4;55(4):698-707. Epub 2019 Sep 4.

Hematology Department, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia.

Health care costs attributed to biologics have increased exponentially in the recent years, thus biosimilars offer a possible solution to limit costs while maintaining safety and efficacy. Reducing expenditure is vital to health care especially in developing countries where affordability and access to health care is a major challenge. We discuss the opportunities and the challenges of biosimilars in the field of hematopoietic cell transplantation (HCT) in low- and lower-middle income countries. Developing countries can potentially invest in the forecasted costs reduction by utilizing biosimilars. This can be used to decrease the costs of procedures such as HCT, which is a rapidly growing field in many developing regions. The introduction of biosimilars in the developing regions faces many challenges which include, but are not limited to: legal and regulatory issues, lack of research infrastructure, and the presence of educational barriers. Thus, collaborative efforts are needed to ensure an effective and safe introduction of biosimilars into low- and lower-middle income countries.
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http://dx.doi.org/10.1038/s41409-019-0658-2DOI Listing
April 2020

Endogenous thrombopoietin levels are elevated following double cord blood unit transplantation.

Bone Marrow Transplant 2020 06 28;55(6):1178-1180. Epub 2019 Aug 28.

Division of Hematology, Massachusetts General Hospital, Boston, MA, United States.

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http://dx.doi.org/10.1038/s41409-019-0652-8DOI Listing
June 2020

Neurological Complications after Allogeneic Transplantation - Can We Do Better?

Acta Haematol 2019 17;142(4):193-194. Epub 2019 Jul 17.

University of Virginia Cancer Center, Charlottesville, Virginia, USA.

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http://dx.doi.org/10.1159/000501297DOI Listing
March 2020

Is anemia a harbinger of poorer outcomes after allogeneic hematopoietic cell transplant?

Bone Marrow Transplant 2020 02 7;55(2):275-277. Epub 2019 Jun 7.

Department of Medicine, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA.

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http://dx.doi.org/10.1038/s41409-019-0588-zDOI Listing
February 2020

Isocitrate dehydrogenase 1 and 2 mutations, 2-hydroxyglutarate levels, and response to standard chemotherapy for patients with newly diagnosed acute myeloid leukemia.

Cancer 2019 02 13;125(4):541-549. Epub 2018 Nov 13.

Massachusetts General Hospital, Boston, Massachusetts.

Background: Acute myeloid leukemia (AML) cells harboring mutations in isocitrate dehydrogenase 1 (IDH1) and isocitrate dehydrogenase 2 (IDH2) produce the oncometabolite 2-hydroxyglutarate (2HG). This study prospectively evaluated the 2HG levels, IDH1/2 mutational status, and outcomes of patients receiving standard chemotherapy for newly diagnosed AML.

Methods: Serial samples of serum, urine, and bone marrow aspirates were collected from patients newly diagnosed with AML, and 2HG levels were measured with mass spectrometry. Patients with baseline serum 2HG levels greater than 1000 ng/mL or marrow pellet 2HG levels greater than 1000 ng/2 × 10 cells, which suggested the presence of an IDH1/2 mutation, underwent serial testing. IDH1/2 mutations and estimated variant allele frequencies were identified. AML characteristics were compared with the Wilcoxon test and Fisher's exact test. Disease-free survival and overall survival (OS) were evaluated with log-rank tests and Cox regression.

Results: Two hundred and two patients were treated for AML; 51 harbored IDH1/2 mutations. IDH1/2-mutated patients had significantly higher 2HG levels in serum, urine, bone marrow aspirates, and aspirate cell pellets than wild-type patients. A serum 2HG level greater than 534.5 ng/mL was 98.8% specific for the presence of an IDH1/2 mutation. Patients with IDH1/2-mutated AML treated with 7+3-based induction had a 2-year event-free survival (EFS) rate of 44% and a 2-year OS rate of 57%. There was no difference in complete remission rates, EFS, or OS between IDH1/2-mutated and wild-type patients. Decreased serum 2HG levels on day 14 as a proportion of the baseline were significantly associated with improvements in EFS (P = .047) and OS (P = .019) in a multivariate analysis.

Conclusions: Among patients with IDH1/2-mutated AML, 2HG levels are highly specific for the mutational status at diagnosis, and they have prognostic relevance in patients receiving standard chemotherapy.
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http://dx.doi.org/10.1002/cncr.31729DOI Listing
February 2019

Third-party fecal microbiota transplantation following allo-HCT reconstitutes microbiome diversity.

Blood Adv 2018 04;2(7):745-753

Blood and Marrow Transplant Program, Massachusetts General Hospital, Boston, MA.

We hypothesized that third-party fecal microbiota transplantation (FMT) may restore intestinal microbiome diversity after allogeneic hematopoietic cell transplantation (allo-HCT). In this open-label single-group pilot study, 18 subjects were enrolled before allo-HCT and planned to receive third-party FMT capsules. FMT capsules were administered no later than 4 weeks after neutrophil engraftment, and antibiotics were not allowed within 48 hours before FMT. Five patients did not receive FMT because of the development of early acute gastrointestinal (GI) graft-versus-host disease (GVHD) before FMT (n = 3), persistent HCT-associated GI toxicity (n = 1), or patient decision (n = 1). Thirteen patients received FMT at a median of 27 days (range, 19-45 days) after HCT. Participants were able to swallow and tolerate all FMT capsules, meeting the primary study endpoint of feasibility. FMT was tolerated well, with 1 treatment-related significant adverse event (abdominal pain). Two patients subsequently developed acute GI GVHD, with 1 patient also having concurrent bacteremia. No additional cases of bacteremia occurred. Median follow-up for survivors is 15 months (range, 13-20 months). The Kaplan-Meier estimates for 12-month overall survival and progression-free survival after FMT were 85% (95% confidence interval, 51%-96%) and 85% (95% confidence interval, 51%-96%), respectively. There was 1 nonrelapse death resulting from acute GI GVHD (12-month nonrelapse mortality, 8%; 95% confidence interval, 0%-30%). Analysis of stool composition and urine 3-indoxyl sulfate concentration indicated improvement in intestinal microbiome diversity after FMT that was associated with expansion of stool-donor taxa. These results indicate that empiric third-party FMT after allo-HCT appears to be feasible, safe, and associated with expansion of recipient microbiome diversity. This trial was registered at www.clinicaltrials.gov as #NCT02733744.
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http://dx.doi.org/10.1182/bloodadvances.2018017731DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5894265PMC
April 2018

Phase 1 study of the Hedgehog pathway inhibitor sonidegib for steroid-refractory chronic graft-versus-host disease.

Blood Adv 2017 Oct 5;1(22):1919-1922. Epub 2017 Oct 5.

Blood and Marrow Transplant Program.

Hedgehog signaling plays a key role in tissue fibrosis, the pathological hallmark of chronic graft-versus-host disease (cGVHD). We conducted a phase 1 trial of sonidegib, a selective antagonist of the hedgehog coreceptor Smoothened, for the treatment of steroid-refractory cGVHD. After a 3+3 study design, sonidegib was administered for up to 12 cycles of 28 days each, using 3 doses: 200 mg/day (dose level 1), 400 mg/day (dose level 2), and 600 mg/day (dose level 3). Seventeen patients were enrolled. The median number of cycles completed was 6 (range, 0-12). There was only 1 dose-limiting toxicity (cohort 2, grade 3 creatine phosphokinase increase) observed. Immunohistochemical evaluation of skin biopsies revealed decreased protein expression of hedgehog signaling pathway molecules with sonidegib therapy. Clinically, 8 patients (47%) had a partial response in skin or sclerodermatous disease, 6 patients had no response, and 3 were not evaluable. Clinical responses were assessed by treating physicians and not by National Institutes of Health criteria. Overall, patients reported worsening of quality of life, which was more severe in clinical nonresponders. Accrual was terminated early as a result of the cumulative toxicity burden not attributed to sonidegib and patient decisions to stop taking sonidegib. We believe hedgehog signaling inhibition warrants further investigation in patients with cGVHD because of the association with clinical responses and immunohistochemical changes. This trial was registered at www.clinicaltrials.gov as #NCT02086513.
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http://dx.doi.org/10.1182/bloodadvances.2017011239DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5728150PMC
October 2017

A phase I study of lenalidomide plus chemotherapy with mitoxantrone, etoposide, and cytarabine for the reinduction of patients with acute myeloid leukemia.

Am J Hematol 2018 02 21;93(2):254-261. Epub 2017 Nov 21.

University of Virginia, Charlottesville, Virginia.

Patients with relapsed AML have a poor prognosis and limited responses to standard chemotherapy. Lenalidomide is an immunomodulatory drug that may modulate anti-tumor immunity. We performed a study to evaluate the safety and tolerability of lenalidomide with mitoxantrone, etoposide and cytarabine (MEC) in relapsed/refractory AML. Adult patients with relapsed/refractory AML were eligible for this phase I dose-escalation study. We enrolled 35 patients using a "3 + 3" design, with a 10 patient expansion cohort at the maximum tolerated dose (MTD). Lenalidomide was initially given days 1-14 and MEC days 4-8; due to delayed count recovery, the protocol was amended to administer lenalidomide days 1-10. The dose of lenalidomide was then escalated starting at 5 mg/d (5-10-25-50). The primary objective was tolerability and MTD determination, with secondary outcomes including overall survival (OS). The MTD of lenalidomide combined with MEC was 50 mg/d days 1-10. Among the 35 enrolled patients, 12 achieved complete remission (CR) (34%, 90%CI 21-50%); 30-day mortality was 6% and 60-day mortality 13%. The median OS for all patients was 11.5 months. Among 17 patients treated at the MTD, 7 attained CR (41%); the median OS was not reached while 12-month OS was 61%. Following therapy with MEC and lenalidomide, patient CD4+ and CD8+ T-cells demonstrated increased inflammatory responses to autologous tumor lysate. The combination of MEC and lenalidomide is tolerable with an RP2D of lenalidomide 50 mg/d days 1-10, yielding encouraging response rates. Further studies are planned to explore the potential immunomodulatory effect of lenalidomide and MEC.
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http://dx.doi.org/10.1002/ajh.24968DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6290473PMC
February 2018

Cabozantinib is well tolerated in acute myeloid leukemia and effectively inhibits the resistance-conferring FLT3/tyrosine kinase domain/F691 mutation.

Cancer 2018 01 28;124(2):306-314. Epub 2017 Sep 28.

Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland.

Background: Cabozantinib, a tyrosine kinase inhibitor of FMS-like tyrosine kinase 3 (FLT3), MET, AXL, vascular endothelial growth factor receptor, and KIT, is approved for use in multiple malignancies. We assessed the safety and tolerability of cabozantinib in AML, given up-regulation of multiple relevant pathways.

Methods: Adults were eligible if they were 18 years old or older with relapsed/refractory AML or if they were 70 years old or older with newly diagnosed AML but were ineligible for conventional therapy. Cabozantinib was administered in 28-day cycles, and dose escalation occurred via cohorts. A pharmacodynamic evaluation of serial plasma samples via a plasma inhibitory assay (PIA) was used to assess FLT3-inhibitory activity in FLT3-mutant cell lines.

Results: Among 18 patients enrolled, 5 were found to harbor FLT3/ITD mutations. Sixteen patients (89%) had relapsed/refractory AML, and most were treated with 2 or more lines of prior treatment. No dose-limiting toxicities (DLTs) were detected at the first dose level (40 mg daily), but 2 patients experienced DLTs at the next level (60 mg daily). The remaining patients were then dosed at 40 mg daily, the maximum tolerated dose (MTD). Additional grade 2 or higher toxicities, possibly/probably related to cabozantinib, included fatigue, nausea, transaminitis, and electrolyte imbalance. No patients had a marrow response according to formal criteria, but 4 had peripheral blast reductions; 2 of these 4 patients transiently cleared circulating blasts. One patient experienced a reduction in marrow blasts, and 1 had stable disease. The FLT3-inhibitory activity of plasma samples, as assessed with the PIA, revealed potent and sustained inhibition in FLT3/ITD and, notably, F691 tyrosine kinase domain (TKD)-mutant cells.

Conclusions: Cabozantinib is well tolerated in AML patients at an MTD of 40 mg daily and is a potent inhibitor of FLT3/ITD- and F691 TKD-altered tyrosine kinases. Cancer 2018;124:306-14. © 2017 American Cancer Society.
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http://dx.doi.org/10.1002/cncr.31038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8167813PMC
January 2018

Increasing use of allogeneic hematopoietic cell transplantation in patients aged 70 years and older in the United States.

Blood 2017 08 3;130(9):1156-1164. Epub 2017 Jul 3.

Seidman Cancer Center, University Hospitals Cleveland Medical Center, Cleveland, OH.

In this study, we evaluated trends and outcomes of allogeneic hematopoietic cell transplantation (HCT) in adults ≥70 years with hematologic malignancies across the United States. Adults ≥70 years with a hematologic malignancy undergoing first allogeneic HCT in the United States between 2000 and 2013 and reported to the Center for International Blood and Marrow Transplant Research were eligible. Transplant utilization and transplant outcomes, including overall survival (OS), progression-free survival (PFS), and transplant-related mortality (TRM) were studied. One thousand one hundred and six patients ≥70 years underwent HCT across 103 transplant centers. The number and proportion of allografts performed in this population rose markedly over the past decade, accounting for 0.1% of transplants in 2000 to 3.85% (N = 298) in 2013. Acute myeloid leukemia and myelodysplastic syndromes represented the most common disease indications. Two-year OS and PFS significantly improved over time (OS: 26% [95% confidence interval (CI), 21% to 33%] in 2000-2007 to 39% [95% CI, 35% to 42%] in 2008-2013, < .001; PFS: 22% [16% to 28%] in 2000-2007 to 32% [95% CI, 29% to 36%] in 2008-2013, = .003). Two-year TRM ranged from 33% to 35% and was unchanged over time ( = .54). Multivariable analysis of OS in the modern era of 2008-2013 revealed higher comorbidity by HCT comorbidity index ≥3 (hazard ratio [HR], 1.27; = .006), umbilical cord blood graft (HR, 1.97; = .0002), and myeloablative conditioning (HR, 1.61; = .0002) as adverse factors. Over the past decade, utilization and survival after allogeneic transplant have increased in patients ≥70 years. Select adults ≥70 years with hematologic malignancies should be considered for transplant.
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http://dx.doi.org/10.1182/blood-2017-03-772368DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5580273PMC
August 2017

Alternative Donor Graft Sources for Adults with Hematologic Malignancies: A Donor for All Patients in 2017!

Oncologist 2017 09 25;22(9):1125-1134. Epub 2017 May 25.

Department of Medicine, University of Virginia School of Medicine, and Stem Cell Transplant Program, University of Virginia Cancer Center, Charlottesville, Virginia, USA

Hematopoietic stem cell transplant (HSCT) is potentially curative for a wide variety of malignant diseases, including acute and leukemias, lymphoma, and myelodysplasia. Choice of a stem cell donor is dependent on donor availability, donor compatibility and health, recipient disease type, and recipient condition. Current sources of stem cell donation for HSCT are matched sibling donors (MSDs), matched unrelated donors (MUDs), 1-antigen mismatched unrelated donors (MMUDs), haploidentical donors (haplo), and umbilical cord blood (UCB) units. Historically, preferred donors for HSCT have been human leukocyte antigen (HLA)-matched sibling donors; however, only about 30% of U.S. patients will have a MSD available. The majority of patients referred for HSCT will require an alternative donor graft: MUD, MMUD, UCB, or haplo. The likelihood of finding a MUD varies depending on the ethnicity of the recipient. White Caucasians of European descent have the greatest chance of finding a MUD. Chances of finding a MUD are significantly less for African-American or Hispanic recipients due to HLA polymorphisms. Therefore, MMUD, UCB, and haplo donor graft sources expand the donor pool for recipients who do not have a MSD or MUD available. Given the variety of different donor stem cell sources available today, nearly every patient who needs an allogeneic HSCT has a potential donor in 2017. All transplant-eligible patients with hematologic malignancies should be evaluated by a transplant center to determine if HSCT is a viable treatment option for their underlying disease process.

Implications For Practice: The goal of this review is to increase the awareness of oncology practitioners to the availability of alternative donor stem cell transplants for patients with hematologic malignancies. Despite new agents, stem cell transplant remains the only curative therapy for many patients with acute and chronic leukemia, myelodysplasia, and lymphoma. Given the variety of different donor stem cell sources available today, nearly every patient who needs an allogeneic stem cell transplant will have a donor.
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http://dx.doi.org/10.1634/theoncologist.2017-0009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5599191PMC
September 2017

A multicenter, retrospective, case-cohort study of the epidemiology and risk factors for Clostridium difficile infection among cord blood transplant recipients.

Transpl Infect Dis 2017 Aug 12;19(4). Epub 2017 Jul 12.

Harvard Medical School, Boston, MA, USA.

Background: Clostridium difficile infection (CDI) is the leading cause of health-care associated infectious diarrhea. The aim of this study was to evaluate the epidemiology and risk factors for CDI in the 100 days following umbilical cord blood transplantation (UCBT) at three Boston hospitals.

Methods: We performed a multicenter, retrospective, case-cohort study of 226 UCBT recipients at Beth Israel Deaconess Medical Center, Massachusetts General Hospital, and Dana Farber/Brigham and Women's Cancer Center from 2003 to 2012. CDI was defined as diarrhea (≥3 unformed bowel movements for at least 2 days) plus a positive stool test for toxinogenic C. difficile and not attributed to any other cause.

Results: Among 226 UCBT recipients, 22 patients (9.7%) developed CDI within the first 100 days of transplant (corresponding to an infection rate of 10.8 cases per 10 000 person-days). The 100-day and 1-year rates were stable across the time period and between institutions. UCBT recipients with CDI were more likely than non-CDI patients to be older, with higher body mass indices, and to have received an antipseudomonal penicillin agent. In a time-dependent case-cohort analysis of the risk factors associated with CDI in the first 100 days after UCBT, bacterial infection after UCBT was the strongest risk factor for CDI (hazard ratio 2.8; 95% confidence interval 1.08-7.24; P=.03), after adjustment for transplant variables including antibiotic exposure.

Conclusion: This study verifies the previously reported risk factors for CDI including older age and antibiotic exposure and identifies a novel association between bacterial infections and risk for CDI.
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http://dx.doi.org/10.1111/tid.12728DOI Listing
August 2017

Association between insurance status at diagnosis and overall survival in chronic myeloid leukemia: A population-based study.

Cancer 2017 Jul 2;123(13):2561-2569. Epub 2017 May 2.

Massachusetts General Hospital, Boston, Massachusetts.

Background: Chronic myeloid leukemia (CML) can be treated effectively with tyrosine kinase inhibitor therapy directed at BCR-ABL, but access to care, medication cost, and adherence may be barriers to treatment. This study was designed to determine whether the insurance status at diagnosis influences CML patient outcomes.

Methods: The Surveillance, Epidemiology, and End Results database was used to identify 5784 patients, aged 15 years or older, who were diagnosed with CML between 2007 and 2012 and whose insurance status was documented at diagnosis. The primary outcome was 5-year overall survival (OS). Covariates of interest included the age at diagnosis, race, ethnicity, sex, county-level socioeconomic status, and marital status. OS was evaluated with a log-rank test and Kaplan-Meier estimates.

Results: Among patients aged 15 to 64 years, insurance status was associated with OS (P < .001): being uninsured or having Medicaid was associated with worse 5-year OS in comparison with being insured (uninsured patients, 72.7%; Medicaid patients, 73.1%; insured patients, 86.6%). For patients who were 65 years old or older, insurance had less of an impact on OS (P = .07), with similar 5-year OS rates for patients with Medicaid and those with other insurance (40.2% vs 43.4%). In a multivariate analysis of patients aged 15 to 64 years, both uninsured patients (hazard ratio [HR], 1.93; P < .001) and Medicaid patients (HR, 1.83; P < .001) had an increased hazard of death in comparison with insured patients; patients younger than 40 years, female patients, and married patients also had a lower hazard of death.

Conclusion: These findings suggest that CML patients under the age of 65 years who are uninsured or have Medicaid have significantly worse survival than patients with other insurance coverage. Cancer 2017;123:2561-69. © 2017 American Cancer Society.
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http://dx.doi.org/10.1002/cncr.30639DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5474167PMC
July 2017

Outcomes after Umbilical Cord Blood Transplantation for Myelodysplastic Syndromes.

Biol Blood Marrow Transplant 2017 Jun 10;23(6):971-979. Epub 2017 Mar 10.

Division of Hematology, Oncology and Transplantation, Department of Medicine, University of Minnesota Medical Center, Minneapolis, Minnesota.

For patients with hematologic malignancies undergoing allogeneic hematopoietic cell transplantation, umbilical cord blood transplantation (UCBT) has become an acceptable alternative donor source in the absence of a matched sibling or unrelated donor. To date, however, there have been few published series dedicated solely to describing the outcomes of adult patients with myelodysplastic syndrome (MDS) who have undergone UCBT. Between 2004 and 2013, 176 adults with MDS underwent UCBT as reported to the Center for International Blood and Marrow Transplant Research. Median age at the time of transplantation was 56 years (range, 18-73 years). The study group included 10% with very low, 23% with low, 19% with intermediate, 19% with high, and 13% with very high-risk Revised International Prognostic Scoring System (IPSS-R) scores. The 100-day probability of grade II-IV acute graft-versus-host disease (GVHD) was 38%, and the 3-year probability of chronic GVHD was 28%. The probabilities of relapse and transplantation-related mortality (TRM) at 3 years were 32% and 40%, respectively, leading to a 3-year disease-free survival (DFS) of 28% and an overall survival (OS) of 31%. In multivariate analysis, increasing IPSS-R score at the time of HCT was associated with inferior TRM (P = .0056), DFS (P = .018), and OS (P = .0082), but not with GVHD or relapse. The presence of pretransplantation comorbidities was associated with TRM (P = .001), DFS (P = .02), and OS (P = .001). Reduced-intensity conditioning was associated with increased risk of relapse (relative risk, 3.95; 95% confidence interval, 1.78-8.75; P < .001), and although a higher proportion of myeloablative UCBTs were performed in patients with high-risk disease, the effect of conditioning regimen intensity was the same regardless of IPSS-R score. For some individuals who lack a matched sibling or unrelated donor, UCBT can result in long-term DFS; however, the success of UCBT in this population is hampered by a high rate of TRM.
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http://dx.doi.org/10.1016/j.bbmt.2017.03.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5474679PMC
June 2017

Phase I study of the aurora A kinase inhibitor alisertib with induction chemotherapy in patients with acute myeloid leukemia.

Haematologica 2017 04 29;102(4):719-727. Epub 2016 Dec 29.

Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, USA.

Aberrant expression of aurora kinase A is implicated in the genesis of various neoplasms, including acute myeloid leukemia. Alisertib, an aurora A kinase inhibitor, has demonstrated efficacy as monotherapy in trials of myeloid malignancy, and this efficacy appears enhanced in combination with conventional chemotherapies. In this phase I, dose-escalation study, newly diagnosed patients received conventional induction with cytarabine and idarubicin, after which alisertib was administered for 7 days. Dose escalation occurred cohorts. Patients could then receive up to four cycles of consolidation, incorporating alisertib, and thereafter alisertib maintenance for up to 12 months. Twenty-two patients were enrolled. One dose limiting toxicity occurred at dose level 2 (prolonged thrombocytopenia), and the recommended phase 2 dose was established at 30mg twice daily. Common therapy-related toxicities included cytopenias and mucositis. Only three (14%) patients had persistent disease at mid-cycle, requiring "5+2" reinduction. The composite remission rate (complete remission and complete remission with incomplete neutrophil recovery) was 86% (nineteen of twenty-two patients; 90% CI 68-96%). Among those over age 65 and those with high-risk disease (secondary acute leukemia or cytogenetically high-risk disease), the composite remission rate was 88% and 100%, respectively. The median follow up was 13.5 months. Of those treated at the recommended phase 2 dose, the 12-month overall survival and progression-free survival were 62% (90% CI 33-81%) and 42% (90% CI 17-65%), respectively. Alisertib is well tolerated when combined with induction chemotherapy in acute myeloid leukemia, with a promising suggestion of efficacy. ().
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http://dx.doi.org/10.3324/haematol.2016.158394DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5395112PMC
April 2017