Amy E. DeZern

Risk-stratified outcomes of nonmyeloablative HLA-haploidentical BMT with high-dose posttransplantation cyclophosphamide

Related HLA-haploidentical blood or marrow transplantation (BMT) with high-dose posttransplantation cyclophosphamide (PTCy) is being increasingly used because of its acceptable safety profile. To better define outcomes of nonmyeloablative (NMA) HLA-haploidentical BMT with PTCy, 372 consecutive adult hematologic malignancy patients who underwent this procedure were retrospectively studied. Risk-stratified outcomes were evaluated using the refined Disease Risk Index (DRI), developed to stratify disease risk across histologies and allogeneic BMT regimens. Patients received uniform conditioning, T-cell-replete allografting, then PTCy, mycophenolate mofetil, and tacrolimus. Six-month probabilities of nonrelapse mortality and severe acute graft-versus-host disease were 8% and 4%. With 4.1-year median follow-up, 3-year probabilities of relapse, progression-free survival (PFS), and overall survival (OS) were 46%, 40%, and 50%, respectively. By refined DRI group, low (n = 71), intermediate (n = 241), and high/very high (n = 60) risk groups had 3-year PFS estimates of 65%, 37%, and 22% (P < .0001), with corresponding 3-year OS estimates of 71%, 48%, and 35% (P = .0001). On multivariable analyses, the DRI was statistically significantly associated with relapse, PFS, and OS (each P < .001). This analysis demonstrates that the DRI effectively risk stratifies recipients of NMA HLA-haploidentical BMT with PTCy and also suggests that this transplantation platform yields similar survivals to those seen with HLA-matched BMT.

Outcomes of Nonmyeloablative HLA-Haploidentical Blood or Marrow Transplantation With High-Dose Post-Transplantation Cyclophosphamide in Older Adults

PURPOSE Recent advances in nonmyeloablative (NMA), related HLA-haploidentical blood or marrow transplantation (haplo-BMT) have expanded the donor pool. This study evaluated the effect of age on NMA haplo-BMT outcomes in patients age 50 to 75 years. PATIENTS AND METHODS A retrospective analysis was performed of 271 consecutive patients with hematologic malignancies, age 50 to 75 years, who received NMA, T-cell-replete haplo-BMT with high-dose post-transplantation cyclophosphamide. RESULTS The median age was 61 years, with 115 patients (42%) age 50 to 59, 129 (48%) age 60 to 69, and 27 (10%) age 70 to 75 years. Overall, 84% of patients had intermediate- or high-/very high-risk disease. The 6-month probabilities of grade 3 or 4 acute graft-versus-host disease (GVHD) and nonrelapse mortality (NRM) were 3% and 8%, respectively. Patients in their 50s, 60s, and 70s had 6-month NRM probabilities of 8%, 9%, and 7%, respectively (P=.20). With a median follow-up of 4 years, corresponding 3-year progression-free survival probabilities were 39%, 35%, and 33% (P=.65), and corresponding 3-year overall survival probabilities were 48%, 45%, and 44% (P=.66). Three-year progression-free survival probabilities were 40% in acute myeloid leukemia (n=65), 39% in aggressive non-Hodgkin lymphoma (n=83), and 37% in indolent or mantle-cell lymphoma (n=65). Older patient age was associated with a significantly higher risk of grade 2 to 4 acute GVHD but not grade 3 to 4 acute or chronic GVHD. No statistically significant associations were found between older age (relative to age 50 to 59 years or as a continuous variable) and NRM, relapse, or survival. CONCLUSION NMA haplo-BMT with post-transplantation cyclophosphamide has encouraging safety and survival outcomes in patients age 50 to 75 years. In patients otherwise fit for BMT, the results support consideration of this approach despite advanced age.

Role of Allogeneic Transplantation for FLT3/ITD Acute Myeloid Leukemia: Outcomes from 133 Consecutive Newly Diagnosed Patients from a Single Institution

Acute myelogenous leukemia (AML) patients with FLT3/ITD mutations have an inferior survival compared to AML patients with wild-type (WT) FLT3, primarily because of an increased relapse rate. Allogeneic transplantation represents a postremission therapy that is effective at reducing the risk of relapse for many cases of poor-risk AML. Whether or not allogeneic transplantation in first complete remission (CR) can improve outcomes for patients with FLT3/ITD AML remains controversial. Our institution has adopted a policy of pursuing allogeneic transplantation, including the use of alternate donors, for FLT3/ITD AML patients in remission. As part of an instituional review board-approved study, we performed a review of the clinical data from November 1, 2004, to October 31, 2008, on all adult patients under the age of 60 presenting in consecutive fashion to the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins with newly diagnosed non-M3 AML. We followed their outcomes through August 1, 2010. During the study period, 133 previously untreated AML patients between the ages of 20 and 59 were diagnosed and received induction and consolidation therapy at our institution. Of these 133 patients, 31 (23%) harbored an FLT3/ITD mutation at diagnosis. The median overall survival (OS) from the time of diagnosis for the FLT3/ITD AML patients was compared to the OS of the entire cohort and found to be comparable (19.3 months versus 15.5 months, P = .56). Historically, OS for FLT3/ITD AML patients is significantly worse than for AML patients lacking this mutation. However, the OS for the 31 FLT3/ITD patients reported here was comparable to the 102 patients with WT FLT3 over the same 4-year time period. One difference that might have contributed to the surprising outcomes for the FLT3/ITD group is our aggressive pursuit of allogeneic bone marrow transplant (BMT) in CR1 within this group (60% of FLT3/ITD versus 17% with WT). Our single-institution study of consecutively treated AML patients supports the hypothesis that allogeneic transplant in early CR1 improves the long-term outcomes for FLT3/ITD AML.

Single-agent GVHD prophylaxis with posttransplantation cyclophosphamide after myeloablative, HLA-matched BMT for AML, ALL, and MDS

High-dose, posttransplantation cyclophosphamide (PTCy) reduces severe graft-versus-host disease (GVHD) after allogeneic blood or marrow transplantation (alloBMT), but the impact of PTCy on long-term, disease-specific outcomes is unclear. We conducted a retrospective study of 209 consecutive adult patients transplanted for acute myeloid leukemia (AML, n = 138), myelodysplastic syndrome (n = 28), or acute lymphoblastic leukemia (ALL, n = 43) using PTCy as sole GVHD prophylaxis after myeloablative conditioning and HLA-matched-related or -unrelated T-cell-replete allografting. At alloBMT, 30% of patients were not in morphologic complete remission. The cumulative incidences of grades II to IV and III to IV acute GVHD at 100 days and chronic GVHD at 2 years were 45%, 11%, and 13%, respectively. Forty-three percent of patients did not require immunosuppression for any reason beyond PTCy. At 3 years, relapse cumulative incidence was 36%, disease-free survival was 46%, survival free of disease and chronic GVHD was 39%, and overall survival was 58%. Lack of remission at alloBMT, adverse cytogenetics, and low allograft nucleated cell dose were associated with inferior survival for AML patients. Minimal residual disease but not t(9;22) was associated with inferior outcomes for ALL patients. The ability to limit posttransplantation immunosuppression makes PTCy a promising transplantation platform for the integration of postgrafting strategies to prevent relapse.

Loss-of-function mutations in the RNA biogenesis factor NAF1 predispose to pulmonary fibrosis–emphysema

Mutations in the RNA biogenesis factor NAF1 cause short telomeres and, consequently, age-related lung disease in people. Tidy telomeres make for healthier lungs Telomeres are the protective caps that prevent the ends of chromosomes from unraveling. People carrying mutations in the protein or RNA component of telomerase, the enzyme that makes telomeres have short telomeres and a serious and often fatal lung disease—pulmonary fibrosis. Now, Stanley et al. find in several patients that other mutations, specifically those that interfere with RNA biogenesis, can also cause both short telomeres and lung disease. This work expands our understanding of how telomeres are maintained and their role in human disease. Chronic obstructive pulmonary disease and pulmonary fibrosis have been hypothesized to represent premature aging phenotypes. At times, they cluster in families, but the genetic basis is not understood. We identified rare, frameshift mutations in the gene for nuclear assembly factor 1, NAF1, a box H/ACA RNA biogenesis factor, in pulmonary fibrosis–emphysema patients. The mutations segregated with short telomere length, low telomerase RNA levels, and extrapulmonary manifestations including myelodysplastic syndrome and liver disease. A truncated NAF1 was detected in cells derived from patients, and, in cells in which the frameshift mutation was introduced by genome editing, telomerase RNA levels were reduced. The mutant NAF1 lacked a conserved carboxyl-terminal motif, which we show is required for nuclear localization. To understand the disease mechanism, we used CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 (CRISPR-associated protein-9 nuclease) to generate Naf1+/− mice and found that they had half the levels of telomerase RNA. Other box H/ACA RNA levels were also decreased, but rRNA pseudouridylation, which is guided by snoRNAs, was intact. Moreover, first-generation Naf1+/− mice showed no evidence of ribosomal pathology. Our data indicate that disease in NAF1 mutation carriers is telomere-mediated; they show that NAF1 haploinsufficiency selectively disturbs telomere length homeostasis by decreasing the levels of telomerase RNA while sparing rRNA pseudouridylation.

Comparable composite endpoints after HLA-matched and HLA-haploidentical transplantation with post-transplantation cyclophosphamide

Composite endpoints that not only encompass mortality and relapse, but other critical post-transplant events such as graft-versus-host disease, are being increasingly utilized to quantify survival without significant morbidity after allogeneic blood or marrow transplantation. High-dose, post-transplantation cyclophosphamide reduces severe graft-versus-host disease with allogeneic marrow transplantation, making composite endpoints after this management particularly interesting. We retrospectively analyzed 684 adults with hematologic malignancies who received T-cell-replete bone marrow grafts and cyclophosphamide after myeloablative HLA-matched related (n=192) or unrelated (n=120), or non-myeloablative HLA-haploidentical (n=372) donor transplantation. The median follow up was 4 (range, 0.02–11.4) years. Graft-versus-host disease-free, relapse-free survival was defined as the time after transplantation without grade III–IV acute graft-versus-host disease, chronic graft-versus-host disease requiring systemic treatment, relapse, or death. Chronic graft-versus-host disease-free, relapse-free survival was defined as the time after transplantation without moderate or severe chronic graft-versus-host disease, relapse, or death. One-year graft-versus-host disease-free, relapse-free survival and chronic graft-versus-host disease-free, relapse-free survival estimates were, respectively, 47% (95% CI: 41–55%) and 53% (95% CI: 46–61%) after myeloablative HLA-matched related, 42% (95% CI: 34–52%) and 52% (95% CI: 44–62%) after myeloablative HLA-matched unrelated, and 45% (95% CI: 40–50%) and 50% (95% CI: 45–55%) after non-myeloablative HLA-haploidentical donor transplantation. In multivariable models, there were no differences in graft-versus-host disease-free, or chronic graft-versus-host disease-free, relapse-free survival after either myeloablative HLA-matched unrelated or non-myeloablative HLA-haploidentical, compared with myeloablative HLA-matched related donor transplantation. Although limited by inclusion of dissimilar cohorts, we found that post-transplantation cyclophosphamide-based platforms yield comparable composite endpoints across conditioning intensity, donor type, and HLA match.

A Multi-Institution Phase I Trial of Ruxolitinib in Patients with Chronic Myelomonocytic Leukemia (CMML)

Purpose: To conduct a phase I clinical trial exploring the safety and efficacy of ruxolitinib, a JAK1/2 inhibitor, for chronic myelomonocytic leukemia (CMML). Experimental Design: Patients with CMML-1 were included without regard to previous therapy. Key exclusion criteria included an absolute neutrophil count (ANC) <0.25 × 103 cells/dL and a platelet count <35 × 103 cells/dL. Four cohorts were enrolled using a “rolling six” study design, with doses ranging from 5 to 20 mg twice daily of ruxolitinib in 5-mg dose escalations. Results: Between March 2013 and January 2015, 20 patients were enrolled and treated with ruxolitinib. Seventy percent of patients had the proliferative subtype and 47% had higher risk disease by the Global MD Anderson Scoring System. Eight patients (42%) received a prior hypomethylating agent. No dose-limiting toxicities for ruxolitinib were identified. One subject had grade (G)3 thrombocytopenia with no other drug-associated G3 or G4 adverse events. The mean duration of therapy was 122 days (range, 28–409 days). Four had hematologic improvement and one patient had a partial response per 2006 International Working Group (IWG) criteria. Five of 9 patients with splenomegaly had a reduction in spleen size. Ten of 11 patients with reported disease-related symptoms had clinically meaningful or complete resolution. When combining IWG and spleen responses, a total response rate of 35% (n = 7) was identified. Correlative analysis demonstrated a reduction in inflammatory cytokines and GM-CSF–dependent STAT5 phosphorylation. Conclusions: The recommended phase II dose of ruxolitinib is 20 mg twice daily. We demonstrate that ruxolitinib has promising activity in CMML with particular benefit in those with disease-related B symptoms that warrants further study. Clin Cancer Res; 22(15); 3746–54. ©2016 AACR. See related commentary by Solary, p. 3707

Risk‐adjusted clinical outcomes in patients enrolled in a bloodless program

Although clinical outcomes have been reported for patients who do not accept allogeneic blood transfusion (ABT), many previous studies lack a control group, fail to use risk adjustment, and focus exclusively on cardiac surgery.

Predictors of hemoglobin response to eculizumab therapy in paroxysmal nocturnal hemoglobinuria

Paroxysmal nocturnal hemoglobinuria (PNH) is a clonal, hematopoietic stem cell disorder that manifests with hemolytic anemia and bone marrow failure. Eculizumab has been shown to improve anemia, decrease intravascular hemolysis, and reduce the risk of thrombosis.

Hepatopulmonary syndrome is a frequent cause of dyspnea in the short telomere disorders.

BACKGROUND Telomere syndromes have their most common manifestation in idiopathic pulmonary fibrosis and emphysema. The short telomere defect in these patients may manifest systemically as bone marrow failure and liver disease. We sought to understand the causes of dyspnea in telomerase and telomere gene mutation carriers who have no parenchymal lung disease. METHODS Clinical and pathologic data were reviewed as part of a Johns Hopkins-based natural history study of short telomere syndromes including dyskeratosis congenita. RESULTS Hepatopulmonary syndrome (HPS) was diagnosed in nine of 42 cases (21%). Their age at presentation was significantly younger than that of cases initially presenting with pulmonary fibrosis and emphysema (median, 25 years vs 55 years; P < .001). Cases had evidence of intra- and extrapulmonary arteriovascular malformations that caused shunt physiology. Nodular regenerative hyperplasia was the most frequent histopathologic abnormality, and it was seen in the absence of cirrhosis. Dyspnea and portal hypertension were progressive, and the median time to death or liver transplantation was 6 years (range, 4-10 years; n = 6). In cases that underwent liver transplantation, dyspnea and hypoxia improved, but pulmonary fibrosis subsequently developed. CONCLUSIONS This report identifies HPS as a frequent cause of dyspnea in telomerase and telomere gene mutation carriers. While it usually precedes the development of parenchymal lung disease, HPS may also co-occur with pulmonary fibrosis and emphysema. Recognizing this genetic diagnosis is critical for management, especially in the lung and liver transplantation setting.