Prophylactic Pretransplant Ganciclovir to Reduce Cytomegalovirus Infection After Hematopoietic Stem Cell Transplantation.

OBJECTIVE/BACKGROUND: Cytomegalovirus (CMV) reactivation remains a serious complication after allogeneic hematopoietic cell transplantation (HCT) occurring in approximately 60-70% of CMV-seropositive HCT recipients. CMV reactivation leads to adverse outcomes including end-organ damage, graft-versus-host disease, and graft failure. METHODS: Ganciclovir was administered pretransplant at 5 mg/kg twice daily intravenously from the start of conditioning to Day T-2 to CMV-seropositive patients receiving their first allogeneic HCT. CMV DNA was monitored weekly until at least Day 100 posttransplant. RESULTS: A total of 109 consecutive patients were treated, median age 57 (range 20-73) years. Of these, 36 (33%) patients had a CMV reactivation within the first 105 days posttransplant with a median time of reactivation of 52.5 (range 36-104) days posttransplant. The cumulative incidence of CMV reactivation at Day 105 posttransplant was 33.1% (95% confidence interval: 24.4-42.0). One patient developed CMV disease. CONCLUSION: The use of pretransplant ganciclovir was associated with low incidence of CMV reactivation and disease. These data suggest that pretransplant ganciclovir with preemptive therapy for viral reactivation may be a useful strategy to reduce CMV reactivation. Future prospective trials are needed to compare strategies for CMV prophylaxis.

Blood and Marrow Transplant Clinical Trials Network State of the Science Symposium 2021: Looking Forward as the Network Celebrates its 20th Year.

In 2021 the BMT CTN held the 4th State of the Science Symposium where the deliberations of 11 committees concerning major topics pertinent to a particular disease, modality, or complication of transplant, as well as two committees to consider clinical trial design and inclusion, diversity, and access as cross-cutting themes were reviewed. This article summarizes the individual committee reports and their recommendations on the highest priority questions in hematopoietic stem cell transplant and cell therapy to address in multicenter trials.

Comparison of haploidentical and umbilical cord blood transplantation after myeloablative conditioning.

Haploidentical hematopoietic stem cell transplantation (haplo-HSCT) has emerged as an important treatment modality. Most reports comparing haplo-HSCT with posttransplant cyclophosphamide (PTCy) and other donor sources have focused on outcomes in older adults treated with reduced intensity conditioning. Therefore, in the current study, we evaluated outcomes in patients with hematological malignancy treated with myeloablative conditioning prior to haplo- (n = 375) or umbilical cord blood (UCB; n = 333) HSCT. All haplo recipients received a 4 of 8 HLA-matched graft, whereas recipients of UCB were matched at 6-8/8 (n = 145) or ≤5/8 (n = 188) HLA antigens. Recipients of 6-8/8 UCB transplants were younger (14 years vs 21 and 29 years) and more likely to have lower comorbidity scores compared with recipients of ≤5/8 UCB and haplo-HSCT (81% vs 69% and 63%, respectively). UCB recipients were more likely to have acute lymphoblastic leukemia and transplanted in second complete remission (CR), whereas haplo-HSCT recipients were more likely to have acute myeloid leukemia in the first CR. Other characteristics, including cytogenetic risk, were similar. Survival at 3 years was similar for the donor sources (66% haplo- and 61% after ≤5/8 and 58% after 6-8/8 UCB). Notably, relapse at 3 years was lower in recipients of ≤5/8 UCB (21%, P = .03) compared with haplo- (36%) and 6-8/8 UCB (30%). However, nonrelapse mortality was higher in ≤5/8 UCB (21%) compared with other groups (P < .0001). These data suggest that haplo-HSCT with PTCy after myeloablative conditioning provides an overall survival outcome comparable to that after UCB regardless HLA match group.

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

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.

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

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.

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

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.

Umbilical cord blood: The promise and the uncertainty.

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.

MLL-Rearranged Acute Lymphoblastic Leukemia.

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.

Treatment of acute leukaemia in adult Jehovah's Witnesses.

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.

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.

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.

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

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/m2 per day on days 1-7) and intravenous bolus of idarubicin (12 mg/m2 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.

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.

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.

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

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/m2/day, Day -7 to -2), melphalan (100 mg/m2/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.

Correction: 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.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

What have we learned from transplanting older patients?

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.