Jennifer E. Schwartz

In Vivo DPP-4 Inhibition to Enhance Engraftment of Single-Unit Cord Blood Transplants in Adults with Hematological Malignancies

Delayed engraftment is a significant limitation of umbilical cord blood (UCB) transplantation due to low stem cell numbers. Inhibition of dipeptidyl peptidase (DPP)-4 enhanced engraftment in murine transplants. We evaluated the feasibility of systemic DPP-4 inhibition using sitagliptin to enhance engraftment of single-unit UCB grafts in adults with hematological malignancies. Twenty-four patients (21-58 years) received myeloablative conditioning, followed by sitagliptin 600 mg orally days -1 to +2, and single UCB grafts day 0. Seventeen receiving red cell-depleted (RCD) grafts, matched at 4 (n=10) or 5 (n=7) of 6 human leucocyte antigen (HLA) loci with median nucleated cell dose 3.6 (2.5-5.2)×10(7)/kg, engrafted at median of 21 (range, 13-50) days with cumulative incidence of 94% (95% confidence interval, 84%-100%) at 50 days. Plasma DDP-4 activity was reduced to 23%±7% within 2 h. Area under DPP-4 activity-time curve (AUCA) correlated with engraftment; 9 of 11 with AUCA <6,000 activity·h engrafted within ≤21 days, while all 6 with higher AUCA engrafted later (P=0.002). Seven patients receiving red cell replete grafts had 10-fold lower colony forming units after thawing compared with RCD grafts, with poor engraftment. Systemic DPP-4 inhibition was well tolerated and may enhance engraftment. Optimizing sitagliptin dosing to achieve more sustained DPP-4 inhibition may further improve outcome.

Phase I trial and pharmacokinetic study of high-dose clofarabine and busulfan and allogeneic stem cell transplantation in adults with high-risk and refractory acute leukemia

We conducted a phase I trial to determine the maximum tolerated dose (MTD) of clofarabine with high-dose busulfan followed by allogeneic stem cell transplantation (SCT) in patients with high-risk and refractory acute leukemia. Patients received intravenous busulfan 0.8 mg/kg every 6 h on days −6 to −3 and clofarabine 30–60 mg/m2 per day on days −6 to −2. Graft-versus-host disease prophylaxis included sirolimus plus tacrolimus (days −2 to +180). A total of 15 patients, median age 48 (30–58) years, with acute leukemia that was relapsed and refractory (n=8), primary refractory (n=6), or in CR2 (n=1), were treated at four clofarabine dose levels: 30 (n=3), 40 (n=3), 50 (n=3) and 60 mg/m2 per day (n=6) with busulfan. All engrafted, and the MTD was not reached. Grades 3–4 non-hematological toxicities included vomiting (n=3), mucositis (n=9), hand-foot syndrome (n=1), acute renal failure (n=1) and reversible elevation of aspartate aminotransferase/alanine aminotransferase (n=10). The 1-year event-free survival was 53% (95% confidence interval: 33–86%), and the 1-year overall survival was 60% (95% confidence interval: 40–91%). Given the good tolerability and promising results, we recommend clofarabine 60 mg/m2 per day × 5 days as a phase II dose in combination with busulfan (12.8 mg per kg total dose) for further study as a myeloablative regimen for allogeneic SCT for high-risk acute leukemia.

Long-term disease-free survival after nonmyeloablative cyclophosphamide/fludarabine conditioning and related/unrelated allotransplantation for acute myeloid leukemia/myelodysplasia.

A total of 50 consecutive patients (median age, 57.5 years) with AML (n=30) or myelodysplasia (MDS, n=20) underwent HLA matched related donor (MRD, n=27) or unrelated donor (MUD, n=23) peripheral blood hematopoietic cell transplantation after nonmyeloablative CY/fludarabine (Flu) conditioning. GVHD prophylaxis included CsA (n=19)±mycophenolate mofetil (n=31). At a median follow-up of 59 months, 21 patients (42%) were alive without evidence of disease. By Kaplan–Meier analysis, year 1–4 disease-free survival (DFS) and OS estimates were 0.50/0.58, 0.40/0.46, 0.37/0.43 and 0.37/0.41. MUD recipients were engrafted quickly (13.5 days) compared to MRD recipients (16 days) and relapsed/progressed less frequently (P=0.005). Overall grade 3/4 acute GVHD (aGVHD) occurred in 26% in the absence of antecedent mucositis and was associated with chronic GVHD (cGVHD) and poor OS. Extensive cGVHD developed in 51.2% of 100 day survivors. Rates of aGVHD, cGVHD and survival were similar between MRD and MUD recipients. Of 14 survivors with cGVHD, 5 (35.7%) experienced resolution off immunosuppression, suggesting that tolerance with HLA matched grafts is possible at an advanced age by this method. This study provides further evidence for prolonged DFS after CY/Flu MRD allotransplantation for AML/MDS, and extends the findings to older patients and those with unrelated donors.

Histological evaluation of acute mucocutaneous graft-versus-host disease in nonmyeloablative hematologic stem cell transplants with an observation predicting an increased risk of progression to chronic graft-versus-host disease.

The incorporation of nonmyeloablative conditioning prior to the transplantation of allogeneic hematopoietic cells has emerged as an alternative to myeloablative chemo- and/or radiotherapy for the treatment of hematologic malignancies. Graft-versus-host disease (GVHD) remains a significant complication of both types of hematopoietic cell transplantation (HCT). The clinical phenomenon of late-onset (>100 days after HCT) acute GVHD recently has been described following nonmyeloablative allogeneic transplantation (NMAT); however, there has been no detailed histologic description of acute GVHD in this setting. We sought to characterize the histopathologic features of acute GVHD following NMAT. The clinical and pathologic features of 20 patients with acute GVHD following NMAT over a three-year period were reviewed. Late-onset acute GVHD was diagnosed in 10 of 20 patients with a mean onset of 109.8 days (range 8-410 days); eight (40%) of these subjects with acute GVHD also had concomitant histologic features of chronic lichenoid chronic GVHD. Cases with “composite” histologic features were more likely to progress to fully developed chronic GVHD compared to those without this finding (87.5% vs 25%, P < 0.01). These findings support the existence of late-occurring mucocutaneous GVHD after NMAT and define a strong clinical/laboratory predictor for the subsequent development of chronic GVHD. Patients with composite skin GVHD may benefit from an earlier, more aggressive immunosuppressive interventional strategy.

Trimethoprim–sulfamethoxazole‐induced rhabdomyolysis in an allogeneic stem cell transplant patient

P.J. Kiel, N. Dickmeyer, J.E. Schwartz. Trimethoprim–sulfamethoxazole‐induced rhabdomyolysis in an allogeneic stem cell transplant patient.
Transpl Infect Dis 2010: 12: 451–454. All rights reserved

A Phase I Trial of High-Dose Clofarabine, Etoposide, and Cyclophosphamide and Autologous Peripheral Blood Stem Cell Transplantation in Patients with Primary Refractory and Relapsed and Refractory Non-Hodgkin Lymphoma

Clofarabine has significant single-agent activity in patients with indolent and aggressive non-Hodgkin lymphoma and synergizes with DNA-damaging drugs. Treatment, however, may be associated with severe and prolonged myelosuppression. We conducted a phase I trial to determine the maximum tolerated dose (MTD) of clofarabine in combination with high-dose etoposide and cyclophosphamide followed by autologous peripheral blood stem cell transplantation in patients with refractory non-Hodgkin lymphoma (NHL). Patients received clofarabine at 30-70 mg/m(2)/day on days -6 to -2 in successive cohorts, in combination with etoposide 60 mg/kg (day -8), and cyclophosphamide 100 mg/kg (day -6), followed by filgrastim-mobilized PBSC on day 0. Sixteen patients of median age 57 (range: 32-67) years with diffuse large B cell (n = 8), follicular (n = 5), or mantle cell (n = 3) lymphoma that was either primary refractory (n = 2) or relapsed and refractory (n = 14) were treated at 5 clofarabine dose levels: 30 (n = 3), 40 (n = 3), 50 (n = 3), 60 (n = 3), and 70 mg/m(2)/day (n = 4) in combination with etoposide and cyclophosphamide. All patients had grade 4 neutropenia and thrombocytopenia. Grade 3-4 nonhematologic toxicity was evenly distributed across all 5 dose levels, and included diarrhea (n = 3), mucositis (n = 1), nausea (n = 1), reversible elevation of alanine aminotranferease/aspartate aminotransferase (AST/ALT) (n = 1) or bilirubin (n = 1), and hemorrhagic cystitis (n = 1); all resolved by day +30 following transplantation. The MTD was not reached. No treatment-related deaths occurred. At day +30, 13 patients achieved a complete remission (CR) or unconfirmed CR (CR(U)), and 2 patients achieved a partial response, for an overall response rate of 94%. After a median follow-up of 691 days, the 1-year progression-free survival (PFS) and overall survival (OS) were 63% (95% confidence interval [CI]: 43%-91%) and 68% (95% CI: 49%-96%), respectively. We recommend clofarabine 70 mg/m(2)/day × 5 days as a phase II dose in combination with high-dose etoposide and cyclophosphamide for further testing as a preparative regimen in NHL patients undergoing autologous PBSC transplantation.

Chronic steroid‐response pancytopenia and increased bone density due to thromboxane synthase deficiency

Diagnosis of bone marrow failure (BMF) disorders is challenging but essential for optimal patient management. Here, we report a young adult from nonconsanguineous parents with progressive pancytopenia since childhood, bone pain, increased bone density, and haphazard ossification replacing hematopoiesis within the bone marrow. Sequencing revealed two novel biallelic variants of unknown significance within the thromboxane A synthase gene, TBXAS1 (c.266T > C; c.989T > C), bioinformatically predicted to disrupt the protein. TBXAS1 mutations result in Ghosal hematodiaphyseal dysplasia (OMIM 231095), the autosomal recessive syndrome associated with abnormal bone structure and BMF. Identification of the genetic defect prompted steroid therapy leading to resolution of symptoms.

Cyclophosphamide/fludarabine nonmyeloablative allotransplant for acute myeloid leukemia

We compared survival outcomes following myeloablative allotransplant (MAT) or cyclophosphamide/fludarabine (Cy/Flu) nonmyeloablative allotransplant (NMAT) for 165 patients with acute myelogenous leukemia (AML) in remission or without frank relapse. Patients who received NMAT were more likely to be older and have secondary AML and lower performance status. At a median follow‐up of 61 months, median event‐free survival and overall survival survival were not different between NMAT and MAT in univariate as well as multivariate analyses. Cy/Flu NMAT may provide similar disease control and survival when compared with MAT in patients with AML in remission or without frank relapse. Am. J. Hematol. 90:97–99, 2015.

In reply to Gowda et al and to Yudkowsky.

Academic Medicine, Vol. 89, No. 6 / June 2014 835 While We Advocate for Integrated Electronic Medical Records, Continue to Empower Patients and Families To the Editor: Medical students everywhere sympathize with, and likely can unanimously relate to, Mr. Ehrmann’s account of his recent futile attempts to obtain a transfer patient’s medical records that were critical to ongoing treatment. Disjointed systems and unavailable archives regularly drive frustration and delay patient care. With each failed attempt to obtain records, the cycle of redundant diagnostic medicine repeats, as it is currently the only way to serve our patients in real time. I into an HTT exam. However, it is our impression that if the Core + Clusters curriculum is learned, there would be no need for students to perform the HTT in clinical settings. The Core + Clusters curriculum is designed to allow students to identify and perform maneuvers relevant to their particular patient, without the rote learning that the HTT perpetuates. We agree with Dr. Yudkowsky that determining which of these approaches to learning the PE is most effective is testable, and we look forward to further contributions to this area of research.

Survival after nonmyeloablative versus myeloablative allotransplantation for AML/MDS.

6563 Background: Results from the few retrospective studies comparing nonmyeloablative (NMAT) vs conventional myeloablative (CMAT) allotransplant for the treatment of AML/MDS are mixed. METHODS 143 consecutive patients with AML (n=104) or MDS (n=39) underwent HLA-matched allogeneic peripheral hematopoietic cell (PHC, n=119) or bone marrow (BM, n=24) transplantation from a matched related (MRD, n=84) or unrelated (MUD, n=59) donor between January 2000 and June 2010. Patients were treated with CMAT (n=80) or NMAT cyclophosphamide/fludarabine (n=63) conditioning. Among patients with AML, 87 (90.6%) had intermediate/poor risk cytogenetics; among patients with MDS, 32 (84.2%) had intermediate/high IPSS. Patients in frank relapse at transplant were not included. Follow-up was until death or > 120 days. Kaplan-Meier, log-rank and Cox-regression methods were used to retrospectively compare disease/progression free survival (DFS/PFS) and overall survival (OS). RESULTS The distribution of gender, cytogenetic risk (for AML) and donor source (MRD/MUD) were similar between NMAT and CMAT groups. The NMAT group was older (median age 58 vs. 45 years; p<0.001), more likely to have received PHC (98.4% vs. 71.3%; p<0.001) and have MDS (42.9% vs. 15%; p<0.001). Among patients with AML, the CMAT group was more likely to be in 1st remission or untested relapse (69.1% vs. 33.3%, p<0.001); the NMAT group was more likely to be in 2nd or 3rd remission or have uncategorizable remission status owing to concurrent MDS (n=8) or second hematologic condition (n=2). Among patients with MDS, the NMAT group had higher IPSS (median 1.0 vs. 0.5; p=0.004). Nineteen patients (32.8%) in the NMAT group experienced relapse/progression compared to 24 (32.4%) after CMAT; median DFS/PFS were 426 days and 428 days, respectively (p=0.822). The median OS was 597 and 421 days for NMAT and CMAT groups, respectively (p=0.943). After adjusting for age, graft source (PHC/BM), donor source (MRD/MUD) and disease (MDS/AML), DFS/PFS [hazard ratio 0.90 (p=0.777)] and OS [hazard ratio 0.76 (p=0.401)] were not different between groups. CONCLUSIONS NMAT and CMAT conditioning appear to provide equivelent disease control and survival in patients with high risk, low burden AML/MDS.