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Background: Early treatment failure (ETF) in follicular lymphoma (FL), defined as relapse or progression within 2 years of frontline chemoimmunotherapy, is a newly recognized marker of poor survival and identifies a high-risk group of patients with an expected 5-year overall survival (OS) rate of approximately 50%. Transplantation is an established option for relapsed FL, but its efficacy in this specific ETF FL population has not been previously evaluated.Methods: This study compared autologous hematopoietic stem cell transplantation (auto-HCT) with either matched sibling donor (MSD) or matched unrelated donor (MUD) allogeneic hematopoietic cell transplantation (allo-HCT) as the first transplantation approach for patients with ETF FL (age ≥ 18 years) undergoing auto-HCT or allo-HCT between 2002 and 2014. The primary endpoint was OS. The secondary endpoints were progression-free survival, relapse, and nonrelapse mortality (NRM).Results: Four hundred forty FL patients had ETF (auto-HCT, 240; MSD hematopoietic stem cell transplantation [HCT], 105; and MUD HCT, 95). With a median follow-up of 69 to 73 months, the adjusted probability of 5-year OS was significantly higher after auto-HCT (70%) or MSD HCT (73%) versus MUD HCT (49%; P = .0008). The 5-year adjusted probability of NRM was significantly lower for auto-HCT (5%) versus MSD (17%) or MUD HCT (33%; P < .0001). The 5-year adjusted probability of disease relapse was lower with MSD (31%) or MUD HCT (23%) versus auto-HCT (58%; P < .0001).Conclusions: Patients with high-risk FL, as defined by ETF, undergoing auto-HCT for FL have low NRM and a promising 5-year OS rate (70%). MSD HCT has lower relapse rates than auto-HCT but similar OS. Cancer 2018;124:2541-51. © 2018 American Cancer Society. [ABSTRACT FROM AUTHOR]

Allogeneic hematopoietic stem cell transplantation (HSCT) is a potentially curative option for patients with acute myeloid leukemia (AML). Our understanding of the biology of leukemic stem cells has continued to improve over the last decade and risk stratification using cytogenetics and molecular markers have improved our ability to select patients who would benefit from allogeneic transplantation. Results of HSCT have also improved substantitally, extending the potential application of allogeneic transplant to more patients. This review discusses the theoretical aspects of transplant, analyzes clinical results, and provides recommendations for the use of HSCT in AML. Further study of the biology of leukemic stem cells and the role for HSCT is necessary to optimize outcomes in AML patients. S TEM C ELLS 2012;30:1581-1586 [ABSTRACT FROM AUTHOR]

Allogeneic hematopoietic stem cell transplantation (HSCT) is the only known curative therapy for chronic myelogenous leukemia (CML). Failure, because of relapse or nonrelapse mortality (NRM), generally occurs within 3 years of transplantation, but large studies with long-term follow-up are limited. We present mature results in 335 patients with CML who underwent allogeneic bone marrow transplantation (BMT) from HLA-identical siblings following busulfan and cyclophosphamide (BU/Cy2). Two hundred twenty-nine were in chronic phase (CP) and 106 in accelerated or blastic phase at transplantation. Median follow-up exceeded 14 years. The estimated probability of 18-year leukemia-free survival (LFS) for CP patients was 55.6% and for those beyond CP, 10.5%. Of 182 patients who survived leukemia-free at 3 years, the estimated probability of LFS at 18 years was 61.9%. Late relapse (P = .039) and late NRM (P = .008) occurred at higher rates in patients beyond CP at transplantation. There was no plateau in LFS. [Copyright &y& Elsevier]

Abstract: The primary cause of death (COD) provides important information in many studies of hematopoietic stem cell transplantation (HSCT). A panel of experts critically assessed the CODs submitted by 15 transplantation centers for 281 patients who died in a randomized multicenter trial of unrelated HSCT. The panel reviewed the CODs reported by the transplantation centers, which used the Center for International Blood and Marrow Transplant Research and National Marrow Donor Program COD reporting form. The panel determined that the existing criteria for primary and contributing CODs lacked sufficient stringency for uniform interpretation. A hierarchy was developed and applied to the T cell depletion project. Using its scheme, the panel reclassified 157 CODs (56%) reported by the transplantation centers. The changes resulted in increased recognition of graft-versus-host disease as the primary COD and a concomitant decrease in attribution of the primary COD to infection. This algorithm promotes consistent assignment of primary and contributing CODs for patients with leukemia or lymphoma who expire after myeloablative allogeneic HSCT. [Copyright &y& Elsevier]

Abstract: High-dose therapy and autologous hematopoietic stem cell transplantation are standard early treatment of patients with multiple myeloma. Tandem transplantation appears to provide additional benefit, particularly in patients with limited response to initial transplantation. Myeloablative allogeneic transplantation provides the only potential for cure, but has been largely abandoned because of high mortality rates. Newer and better induction regimens, rigorous analysis of results with autologous and allogeneic transplantation, and the development of risk-adapted stratification provide the impetus for this critical evaluation of the role of hematopoietic stem cell transplantation in multiple myeloma. [Copyright &y& Elsevier]

The article summarizes information surrounding hematopoietic stem cell transplantation and discusses the recent progress in the role of this procedure as far as treating malignant and nonmalignant conditions. The primary use for hematopoietic stem cell transplantations are hematologic and lymphoid cancers, as well as many other health risks. Hematopoietic stem-cell transplantation was originally used as a treatment for irradiation injuries and then cancer. Hematopoietic stem cells are found in bone marrow.

A large majority of allogeneic hematopoietic stem cell donations are achieved using granulocyte-colony stimulating factor (G-CSF). G-CSF use has been associated with later development of myelodysplastic syndromes/acute myelogenous leukemia (MDS/AML) in several clinical circumstances. Although clinical data to date have failed to identify any increased incidence of MDS/AML in G-CSF mobilized donors, the quality of these data are insufficient to exclude a long-term risk. Physicians should explain the potential risk to donors, and where appropriate, offer donors the option of marrow donation. [ABSTRACT FROM AUTHOR]

• Bloodless autologous hematopoietic cell transplantation may be safely performed. • Prime hemoglobin with erythropoiesis-stimulating agents before transplant. • Thrombopoietin agonists may be considered to optimize transplant success. Bloodless autologous hematopoietic cell transplantation is associated with risks of severe bleeding and profound anemia. RBC or platelet transfusions are often used to prevent these hematologic complications. However, in patients such as Jehovah's Witnesses who refuse major blood components, the lack of transfusion support is not an absolute contraindication to an autologous hematopoietic cell transplant. Pennsylvania Hospital performed the world's first bloodless hematopoietic cell transplant more than 15 years ago and has gradually improved its technique with a sizable patient population. Erythropoiesis-stimulating agents were successfully employed as part of their pretransplant regimen to prevent severe anemia. Thrombopoietin agonists' potential role in bloodless transplant is also currently being explored. Although there is limited literature, available reports in combination with physiologic reasoning may support the use of these growth factors to promote transplant success. These agents offer potential benefit and may be of utility in minimizing complications of a bloodless transplant. In this review, we summarize the available literature and offer insight into how we may incorporate growth factors to allow bloodless autologous hematopoietic cell transplantation to be an available option to patients who may otherwise be denied. [ABSTRACT FROM AUTHOR]

Highlights • CYP3A5 polymorphisms did not impact i.v. tacrolimus exposure post-transplant. • CYP3A4 and ABCB1 polymorphisms impacted i.v. tacrolimus exposure post-transplant. • ABCB1 2677TT genotype was associated with increased risk of tacrolimus toxicity. • C YP3A4 and ABCB1 C2677T genotyping may help individualize i.v. tacrolimus dosing. • Pharmacogenomic guidelines should acknowledge differences in i.v. versus oral tacrolimus. Abstract Pharmacogenetics influences oral tacrolimus exposure; however, little data exist regarding i.v. tacrolimus. We investigated the impact of genetic polymorphisms in CYP3A4, CYP3A5, and ABCB1 on i.v. tacrolimus exposure and toxicity in adult patients receiving an allogeneic hematopoietic stem cell transplant for hematologic malignancies. Germline DNA was extracted from buccal swabs and genotyped for CYP3A4, CYP3A5, and ABCB1 polymorphisms. Continuous i.v. infusion of tacrolimus.03 mg/kg/day was initiated on day +5 post-transplant, and steady-state blood concentrations were measured 4days later. We evaluated the association between phenotypes and prevalence of nontherapeutic target concentrations (below or above 5 to 15 ng/mL) as well as tacrolimus-related toxicities. Of 63 patients, 28.6% achieved the target concentration; 71.4% were >15ng/mL, which was more common in CYP3A4 intermediate/normal metabolizers (compared with rapid) and those with at least 1 ABCB1 C2677T loss-of-function allele (P <.05). ABCB1 C2677T was significantly associated with concentrations >15ng/mL (odds ratio, 6.2; 95% confidence interval, 1.8 to 23.6; P =.004) and tacrolimus-related toxicities (odds ratio, 7.5; 95% confidence interval, 1.6 to 55.2; P =.02). ABCB1 C2677T and CYP3A4 are important determinants of i.v. tacrolimus exposure, whereas ABCB1 C2677T also impacts tacrolimus-related toxicities in stem cell transplants. [ABSTRACT FROM AUTHOR]

We compared the outcomes of patients age 60-70 years with acute myelogenous leukemia receiving reduced-intensity allogeneic hematopoietic cell transplantation (HCT) in first remission (CR1) reported to the Center for International Blood and Marrow Research (n = 94) with the outcomes in patients treated with induction and postremission chemotherapy on Cancer and Leukemia Group B protocols (n = 96). All patients included had been in CR1 for at least 4 months. The HCT recipients were slightly younger than the chemotherapy patients (median age, 63 years vs 65 years; P < .001), but there were no significant between-group differences in the proportion with therapy-related leukemia or in different cytogenetic risk groups. Time from diagnosis to CR1 was longer for the HCT recipients (median, 44 days vs 38 days; P = .031). Allogeneic HCT was associated with significantly lower risk of relapse (32% vs 81% at 3 years; P < .001), higher nonrelapse mortality (36% vs 4% at 3 years; P < .001), and longer leukemia-free survival (32% vs 15% at 3 years; P = .001). Although overall survival was longer for HCT recipients, the difference was not statistically significant (37% vs 25% at 3 years; P = .08). Our findings suggest that reduced-intensity conditioning allogeneic HCT in patients age 60-70 with acute myelogenous leukemia in CR1 reduces relapse and improves leukemia-free survival. Strategies that reduce nonrelapse mortality may yield significant improvements in overall survival. [ABSTRACT FROM AUTHOR]

Vitamin D (VD) deficiency can cause osteomalacia, bone pain, muscle weakness, fatigue, and increased risk of fracture, and may precipitate or exacerbate osteopenia and osteoporosis. Patients receiving treatment for acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) may have limited exposure to sunlight and often experience gastrointestinal side effects that may decrease their ability to maintain an adequate VD level. We hypothesized that patients with AML and ALL would have a low VD level after allogeneic hematopoietic cell transplant (HCT), and that these patients would have a high incidence of osteoporosis/osteopenia. We therefore studied the incidence of low VD level and low bone mineral density after HCT. Of 289 patients with AML or ALL undergoing HCT between January 1, 2000, and January 31, 2009, at the Cleveland Clinic, 58 (20.1%) patients had VD testing after HCT. Of these, 52 (89.7%) patients had a low VD level, and 6 (10.3%) had a normal level. Most patients with VD testing had graft-versus-host disease (GVHD) and were taking corticosteroids (94.8% and 98.3%, respectively). Of the 49 patients with VD testing who also had bone mineral density testing, 65% had abnormal (low bone density) results. Only 21% of patients with VD testing were taking VD supplements prior to testing, and 65% had an elevated parathyroid hormone level. We found that most patients did not have VD testing after HCT, but those that did were very likely to have a low level and have low bone mineral density. Those with a low VD level were likely to have received corticosteroids, have GVHD, and have an elevated parathyroid hormone (PTH) level. Given the potential morbidity of low VD level, VD deficiency should be considered after HCT. Prospective study of VD level and its impact on morbidity and mortality after HCT is warranted. [Copyright &y& Elsevier]

The poor prognosis of patients with prolymphocytic leukemia (PLL) has led some clinicians to recommend allogeneic hematopoietic cell transplant (HCT). However, the data to support this approach is limited to case-reports and small case series. We reviewed the database of the Center for International Blood and Marrow Transplant Research (CIBMTR) to determine outcomes after allotransplant for patients with PLL. We identified 47 patients with a median age of 54 years (range: 30-75 years). With a median follow-up of 13 months, progression-free survival (PFS) was 33% (95% confidence interval [CI] 20%-47%) at 1 year. The most common cause of death was relapse or progression in 49%. The cumulative incidence of treatment-related mortality (TRM) at 1-year posttransplant was 28%. The small patient population prohibited prognostic factor analysis, but these data support consideration of allotransplant for PLL. Further study of a larger population of patients is needed to determine which patients are more likely to benefit. [Copyright &y& Elsevier]

Unrelated donor (URD) hematopoietic cell transplantation (HCT) can eradicate chronic myelogenous leukemia (CML). It has been postulated that greater donor–recipient histoincompatibility can augment the graft-versus-leukemia (GVL) effect. We previously reported similar, but not equivalent, outcomes of URD versus sibling donor HCT for CML using an older, less precise classification of HLA matching. Here, we used our recently refined HLA-matching classification, which is suitable for interpretation when complete allele-level typing is unavailable, to reanalyze outcomes of previous HCT for CML. We found that using our new matching criteria identifies substantially more frequent mismatching than older, less precise “6 of 6 antigen–matched” URD-HCT. Under the new criteria, only 37% of those previously deemed “HLA- matched” were HLA well matched, and 44% were partially matched. Using our refined matching criteria confirms the greater risk of graft failure in partially matched or mismatched URD–recipient pairs compared with either sibling or well-matched URD–recipient pairs. Acute and chronic graft-versus-host disease (aGVHD, cGVHD) are significantly more frequent with all levels of recategorized URD HLA matching. Importantly, overall survival (OS) and leukemia-free survival (LFS) remain significantly worse after URD-HCT at any matching level. No augmented GVL effect accompanied URD HLA mismatch. Compared with sibling donor transplants, we observed only marginally increased (not statistically significant) risks of relapse in well-matched, partially matched, and mismatched URD-HCT. These data confirm the applicability of revised HLA-matching scheme in analyzing retrospective data sets when fully informative, allele-level typing is unavailable. In this analysis, greater histoincompatibility can augment GVHD, but does not improve protection against relapse; thus the best donor remains the most closely matched donor. [Copyright &y& Elsevier]

Abstract: We studied the role of HLA-matched sibling hematopoietic cell transplantation (HCT) in treating t(8;21) acute myelogenous leukemia (AML) in first remission. Outcomes of 118 patients receiving HCT and reported to the Center for International Blood and Marrow Transplant Research were compared with 132 similar patients receiving chemotherapy selected from 8 German AML Intergroup multicenter trials. Characteristics of the cohorts were similar except that chemotherapy recipients were significantly older. To adjust for time to treatment bias, outcomes were compared using left-truncated Cox regression models. Transplants were associated with higher treatment-related mortality (TRM; relative risk [RR] 6.76, 95% confidence interval [CI] 2.95-15.45, P < .001), lower relapse (RR 0.47, 95% CI 0.25-0.85, P = .01), and similar relapse-free survival (P = .2). Loss of sex chromosomes (LOS) in addition to t(8;21) had a negative impact on overall survival (OS) in patients receiving chemotherapy. Patients without LOS experienced shorter survival after HCT comparing to chemotherapy (RR 3.05, P = .02), whereas patients with LOS had similar survival regardless of postremission therapy. In both cohorts, white blood cell count (WBC) at diagnosis >25 × 109/L was associated with a higher relapse risk (RR = 2.09, P = .03), lower relapse-free (RR = 1.9, P = .008), and OS (RR = 1.91, P = .01). In this cohort of patients with t(8;21) AML, HCT did not improve OS, because reduction of relapse was offset by high TRM. In the group without LOS, survival after chemotherapy was far superior to HCT. These results suggest that patients with t(8;21) AML without poor prognostic factors have higher rates of survival after chemotherapy as a post remission therapy compared to HCT. [Copyright &y& Elsevier]