Hien K. Duong

Peripheral Blood Progenitor Cell Mobilization for Autologous and Allogeneic Hematopoietic Cell Transplantation: Guidelines from the American Society for Blood and Marrow Transplantation

Peripheral blood progenitor cell mobilization practices vary significantly among institutions. Effective mobilization regimens include growth factor alone, chemotherapy and growth factor combined, and, more recently, incorporation of plerixafor with either approach. Many institutions have developed algorithms to improve stem cell mobilization success rates and cost-effectiveness. However, an optimal stem cell mobilization regimen has not been defined. Practical guidelines are needed to address important clinical questions, including which growth factor is optimal, what chemotherapy and dose is most effective, and when to initiate leukapheresis. We present recommendations, based on a comprehensive review of the literature, from the American Society of Blood and Marrow Transplantation.

Single nucleotide polymorphism array lesions, TET2, DNMT3A, ASXL1 and CBL mutations are present in systemic mastocytosis.

We hypothesized that analysis of single nucleotide polymorphism arrays (SNP-A) and new molecular defects may provide new insight in the pathogenesis of systemic mastocytosis (SM). SNP-A karyotyping was applied to identify recurrent areas of loss of heterozygosity and bidirectional sequencing was performed to evaluate the mutational status of TET2, DNMT3A, ASXL1, EZH2, IDH1/IDH2 and the CBL gene family. Overall survival (OS) was analyzed using the Kaplan-Meier method. We studied a total of 26 patients with SM. In 67% of SM patients, SNP-A karyotyping showed new chromosomal abnormalities including uniparental disomy of 4q and 2p spanning TET2/KIT and DNMT3A. Mutations in TET2, DNMT3A, ASXL1 and CBL were found in 23%, 12%, 12%, and 4% of SM patients, respectively. No mutations were observed in EZH2 and IDH1/IDH2. Significant differences in OS were observed for SM mutated patients grouped based on the presence of combined TET2/DNMT3A/ASXL1 mutations independent of KIT (P = 0.04) and sole TET2 mutations (P<0.001). In conclusion, TET2, DNMT3A and ASXL1 mutations are also present in mastocytosis and these mutations may affect prognosis, as demonstrated by worse OS in mutated patients.

Late Acute and Chronic Graft-versus-Host Disease after Allogeneic Hematopoietic Cell Transplantation

Several distinct graft-versus-host disease (GVHD)-related syndromes have been defined by the National Institutes of Health Consensus Conference. We enrolled a prospective cohort of 911 hematopoietic cell transplantation (HCT) recipients at 13 centers between March 2011 and May 2014 to evaluate 4 GVHD syndromes: late acute GVHD (aGVHD), chronic GVHD (cGVHD), bronchiolitis obliterans syndrome, and cutaneous sclerosis. The median age at HCT was 53.7 years. The majority of patients received a peripheral blood stem cell transplant (81%) following nonmyeloablative or reduced-intensity conditioning (55%). Pediatric age group and use of bone marrow and umbilical cord blood grafts were underrepresented in our cohort (≤11%). The cumulative incidence of late aGVHD (late onset and recurrent) was 10% at a median of 5.5 months post-HCT, that of cGVHD was 47% at a median of 7.4 months, that of bronchiolitis obliterans was 3% at a median of 12.2 months, and that of cutaneous sclerosis was 8% at a median onset of 14.0 months. Late aGVHD and bronchiolitis obliterans had particularly high nonrelapse mortality of 23% and 32%, respectively, by 2 years after diagnosis. The probability of late aGVHD- and cGVHD-free, relapse-free survival was 38% at 1 year post-HCT and 26% at 2 years post-HCT. This multicenter prospective study confirms the high rate of late aGVHD and cGVHD syndromes and supports the need for continuous close monitoring and development of more effective GVHD treatment strategies to improve HCT success.

Predicting hematopoietic stem cell mobilization failure in patients with multiple myeloma: A simple method using day 1 CD34+ cell yield

Early and reliable prediction of the likelihood of achieving adequate stem cell collection for autologous stem cell transplantation (ASCT) in patients with multiple myeloma (MM) would improve collection efficiency, prevent unnecessary aphereses, and permit appropriate treatment alterations. No previous study has reported a threshold CD34+ cell collection quantity on Day 1 or 2 of leukapheresis that could predict successful stem cell collection. We performed a retrospective analysis of all MM patients undergoing first attempt of stem cell collection at our institution from 2001 through 2008. Recursive partitioning analysis was used to identify Day 1 or Day 1+2 CD34+ collection quantity that predicted failure to reach target ≥2 × 106 CD34+ cells/kg within five days of collection. Totally, 172 patients were included in the analysis. Patients underwent mobilization with G‐CSF or G‐CSF+ chemotherapy. 23 of 172 patients (13.4%) failed to collect sufficient (≥2 × 106 CD34+ cells/kg) CD34+ cells after five days of apheresis: 22 of 29 who collected ≤0.70 × 106 CD34+ cells/kg and 1 of 143 who collected >0.70 × 106 CD34+ cells/kg (75.9% vs. 0.7%, P < 0.001) on Day 1. Collection failure occurred in 23 of 30 patients who collected ≤1.54 × 106 CD34+ cells/kg and 0 of 142 who collected >1.54 × 106 CD34+ cells/kg (76.7% vs. 0%, P < 0.001) on Days 1 + 2. Day 1 CD34+ cell collection quantity identifies patients unlikely to achieve adequate collection for ASCT. Patients who collect ≤0.70 × 106 CD34+ cells/kg on day 1 could be considered for treatment modifications to improve CD34+ collection, such as early administration of plerixafor or large volume apheresis. J. Clin. Apheresis, 2011.

Ruxolitinib in combination with DNA methyltransferase inhibitors: clinical responses in patients with symptomatic myelofibrosis with cytopenias and elevated blast(s) counts

* Dr. Brady L. Stein and Dr. Ramon V. Tiu share equal senior authorship for this article. Correspondence: Brady L. Stein, MD, Assistant Professor of Medicine, Division of Hematology and Oncology, Department of Medicine, Northwestern Feinberg University School of Medicine, Chicago, IL, USA. Tel: 312-695-6832. Fax: 312-695-7814. E-mail: bstein@nmff .org. Ramon V. Tiu, MD, Assistant Professor of Molecular Medicine, Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA. Tel: 216-444-6730. Fax: 216-636-2498. E-mail: tiur@ccf.org

Cyclosporine in combination with mycophenolate mofetil versus methotrexate for graft versus host disease prevention in myeloablative HLA‐identical sibling donor allogeneic hematopoietic cell transplantation

Graft‐versus‐host disease (GVHD) remains a major cause of morbidity and mortality in allogeneic hematopoietic cell transplantation (HCT) despite current prophylaxis. Methotrexate (MTX) with a calcineurin inhibitor (CNI) is the current standard, however, has several toxicities. Mycophenolate mofetil (MMF) is frequently used in reduced‐intensity HCT, but data in myeloablative transplants is limited. We thus retrospectively identified 241 patients who underwent myeloablative HCT from an HLA‐identical sibling donor; 174 patients received cyclosporine (CSA) + MMF and 67 received CSA+MTX. Patients receiving MMF + CSA had rapid neutrophil (median 11 vs. 19 days with MTX+CSA), and platelet recovery (median 19 vs. 25 days), lower incidence of severe mucositis by OMAS (19% vs. 53%), and shorter length of hospital stay (median 25 vs. 36 days) (P < 0.001 for all comparisons). There were no significant differences in incidence of grade 2–4 (MMF+CSA 37% vs. MTX+CSA 39%) or 3–4 acute GVHD (17% vs. 12%), chronic GVHD (46% vs. 56%), relapse (28% vs. 27%), non‐relapse mortality (20% vs. 27%), or overall survival (47% vs. 44%) (P = NS for all). However, in multivariable analysis, the use of MMF+CSA was associated with an increased risk of severe grade 3–4 acute GVHD (HR 2.92, 95% CI 1.2–7.15, P = 0.019). There were no differences between the two regimens in multivariable analyses for other survival outcomes. This analysis demonstrates that the use of MMF in myeloablative sibling donor transplantation is well tolerated. However, there may be an increased risk of severe GVHD with MMF+CSA compared to MTX+CSA. Further studies evaluating optimal dosing strategies are needed. Am. J. Hematol. 90:144–148, 2015.

Synergistic Effect of Major Histocompatibility Complex Class I–Related Chain A and Human Leukocyte Antigen–DPB1 Mismatches in Association with Acute Graft-versus-Host Disease after Unrelated Donor Hematopoietic Stem Cell Transplantation

The clinical relevance of mismatches at the MHC class I-related chain A (MICA) in hematopoietic stem cell transplantation (HSCT) remains unclear. We investigated the association of MICA donor/recipient mismatch and whether there is an interaction between these and HLA-DPB1 mismatch on clinical outcomes after unrelated donor HSCT. Our study included 227 patients who underwent unrelated donor allogeneic HSCT at our institution between 2000 and 2010. Among these, 177 (78%) received HSCT from a 10/10 HLA-matched donor. MICA genotyping was performed using commercially available kits. In univariable analysis, the risk of grade II to IV acute graft-versus-host disease (GVHD) was greater for patients with MICA mismatch (hazard ratio [HR], 1.73; P = .02) than for those with HLA-DPB1 mismatch (HR, 1.62; P = .07). When MICA and HLA-DPB1 were assessed simultaneously, patients mismatched at both loci had the greatest risk (HR, 2.51; P < .01) and those mismatched at only 1 locus had somewhat greater risk (HR, 1.53; P = .12) than patients matched at both loci; this remained significant in multivariable analysis. The 100-day incidence was 66%, 45%, and 31%, respectively (P = .03). Results were similar for grade III and IV acute GVHD, with 100-day incidence 34%, 16%, and 8% (P = .01). These results are clinically pertinent to donor selection strategies and indicate that patients with mismatch at both MICA and HLA-DPB1 are at increased risk for acute GVHD.

Clinicopathologic and molecular characterization of myeloid neoplasms harboring isochromosome 17(q10).

To the Editor: This is the third in a series of short articles concerning iron deficiency and the role of intravenous (IV) iron. Iron deficiency anemia is nearly ubiquitous in this population [1] and it is the opinion of many key opinion leaders in the field that failure to routinely replace iron intravenously represents and unmet clinical need. In those with uncomplicated iron deficiency without underlying inflammatory disorders which lead to iron restricted erythropoiesis due to hepcidin upregulation, oral iron is effective and inexpensive. Unfortunately, estimates that 70% of those to whom it is prescribed report significant gastrointestinal perturbation, results in significant nonadherence to therapy. Evidence suggests oral iron causes severe adverse invents when inflammatory bowel disease is present and worsens the underlying pathology [2–4]. While some gastroenterologists continue to extol the virtues of low doses of oral iron, even if well tolerated in subjects with quiescent disease, a year of therapy is required to replace stores. European and American guidelines differ. European guidelines state that the preferred route of iron supplementation in inflammatory bowel disease (IBD) is IV, even though some patients will respond to oral iron. IV iron is more effective and better tolerated and improves the quality of life to a greater extent than oral iron supplementation (Grade A) [2]. Absolute indications for IV iron include severe anemia (Hgb <10 g/dl), intolerance of or inappropriate response to oral iron, severe intestinal disease acuity, and concomitant therapy with an erythropoiesis agent or patient preference. Oral iron supplements can be used if absolute indications for IV iron therapy are not met. If oral iron is used, the response and tolerance should be monitored and treatment changed to IV as necessary (Grade C). Because side effects of oral iron are dose related and because its absorption and efficacy are no greater when high doses are used, no more than 100 mg of elemental iron daily should be prescribed (Grade C). American guidelines state, “oral formulations are more convenient and less expensive and may be used as a first-line option for patients whose IBD activity and anemia are mild” [5]. The medical literature is rife with prospective comparative evidence demonstrating superiority of IV iron over oral iron in both efficacy and toxicity. Recent publications support this view [6–8]. With the advent of four new formulations which allow safe and rapid complete replacement dosing in 15–60 min, the failure to routinely administer IV iron to anemic patients with inflammatory bowel disease may represent another unmet clinical need. A recent publication demonstrated that not only does a 15 min infusion of ferric carboxymaltose correct anemia but prevents recurrence of anemia in patients with inflammatory bowel disease [9]. Similar evidence of efficacy has been published with low molecular weight iron dextran [10,11] and ferumoxytol [12]. Although it remains reasonable to try oral iron in those without active disease, considering the litany of gastrointestinal perturbations present in inflammatory bowel disease, even in remission, perhaps it is time for American gastroenterologists to become more congruent with their European colleagues.

Clinical experiences with ruxolitinib in symptomatic patients with myeloproliferative neoplasm with chronic kidney disease

Myelofi brosis (MF) is a Philadelphia chromosome-negative myeloproliferative neoplasm (MPN) characterized by abnormal clonal proliferation of myeloid cells and their precursors in the bone marrow (BM), BM fi brosis, leukoerythroblastosis and clonal cytogenetic/molecular abnormalities. Most patients have symptomatic disease manifested with debilitating constitutional symptoms and complications due to extramedullary hematopoiesis [1]. Ruxolitinib (Jakafi O ),

Spontaneous recovery of severe nilotinib-induced bone marrow aplasia and successful retreatment with dasatinib in a patient with Chronic Phase Chronic Myeloid Leukemia

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm of the pluripotent bone marrow (BM) stem cells and is consistently associated with the breakpoint cluster region – Abelson (BCR – ABL1) fusion gene caused by the Philadelphia chromosome [t(9;22)(q34;q11.2)]. Th is genetic fusion results in persistent tyrosine kinase activation leading to unrestrained cell proliferation and suppression of apoptosis in malignant cells. Tyrosine kinase inhibitors (TKIs) target the BCR – ABL1 protein, which is overexpressed in the hematopoietic progenitor and stem cells of patients with CML. Th ere are currently fi ve US Food and Drug Administration (FDA) approved TKIs for the management of CML: the prototype TKI (imatinib) and four second-generation TKIs (nilotinib, dasatinib, bosutinib and ponatinib). Nilotinib, an orally bioavailable derivative of imatinib, binds to the inactive conformation of ABL1 kinase with higher affi nity than imatinib, and therefore inhibits its catalytic activity with 20 – 30-fold higher potency than imatinib [1,2]. Nilotinib 400 mg twice daily is FDA approved for the treatment of patients with CML in chronic phase (CP) or accelerated phase (AP) who failed treatment with imatinib due to resistance/intolerance, based on a phase II study of 321 patients with CML-CP who failed imatinib [3]. Nilotinib is also approved as a front-line treatment of patients with CML-CP, based on the phase III study called the ENESTnd (Evaluating Nilotinib Effi cacy and Safety in Clinical Trials – Newly Diagnosed Patients) trial [4 – 6]. BM toxicities associated with TKIs aff ect all cell lineages, but are usually dose-dependent and reversible with drug cessation or dose reduction. Th e ENESTnd study showed that nilotinib is well tolerated with an acceptable safety profi le [4]. However, it is recommended that nilotinib treatment should be held for any grade 3 – 4 toxicity and can be resumed with the same dose if recovery occurs within 2 weeks, otherwise dose reduction should be considered [3]. Although myelosuppression is a common adverse event seen in patients