Primary graft failure after myeloablative allogeneic hematopoietic cell transplantation for hematologic malignancies.

Clinical outcomes after primary graft failure (PGF) remain poor. Here we present a large retrospective analysis (n=23,272) which investigates means to prevent PGF and early detection of patients at high risk. In patients with hematologic malignancies, who underwent their first myeloablative allogeneic hematopoietic cell transplantation, PGF was reported in 1278 (5.5%), and there was a marked difference in PGFs using peripheral blood stem cell compared with bone marrow grafts (2.5 vs 7.3%; P<0.001). A fourfold increase of PGF was observed in myeloproliferative disorders compared with acute leukemia (P<0.001). Other risk factors for PGF included recipient age <30, HLA mismatch, male recipients of female donor grafts, ABO incompatibility, busulfan/cyclophosphamide conditioning and cryopreservation. In bone marrow transplants, total nucleated cell doses ⩽2.4 × 10(8) per kg were associated with PGF (odds ratio 1.39; P<0.001). The use of tacrolimus-based immunosuppression and granulocyte colony-stimulating factor were associated with decreased PGF risk. These data, allow clinicians to do more informed choices with respect to graft source, donor selection, conditioning and immunosuppressive regimens to reduce the risk of PGF. Moreover, a novel risk score determined on day 21 post transplant may provide the rationale for an early request for additional hematopoietic stem cells.

Contribution of chemotherapy mobilization to disease control in multiple myeloma treated with autologous hematopoietic cell transplantation.

In patients with multiple myeloma (MM) undergoing autologous hematopoietic cell transplantation (auto-HCT), peripheral blood progenitor cells may be collected following mobilization with growth factor alone (GF) or cytotoxic chemotherapy plus GF (CC+GF). It is uncertain whether the method of mobilization affects post-transplant outcomes. We compared these mobilization strategies in a retrospective analysis of 968 patients with MM from the Center for International Blood and Marrow Transplant Research database who received an auto-HCT in the US and Canada between 2007 and 2012. The kinetics of neutrophil engraftment (⩾0.5 × 10(9)/L) was similar between groups (13 vs 13 days, P=0.69) while platelet engraftment (⩾20 × 10(9)/L) was slightly faster with CC+GF (19 vs 18 days, P=0.006). Adjusted 3-year PFS was 43% (95% confidence interval (CI) 38-48) in GF and 40% (95% CI 35-45) in CC+GF, P=0.33. Adjusted 3-year OS was 82% (95% CI 78-86) vs 80% (95% CI 75-84), P=0.43 and adjusted 5-year OS was 62% (95% CI 54-68) vs 60% (95% CI 52-67), P=0.76, for GF and CC+GF, respectively. We conclude that MM patients undergoing auto-HCT have similar outcomes irrespective of the method of mobilization and found no evidence that the addition of chemotherapy to mobilization contributes to disease control.

Steady-state end-tidal alveolar dead space fraction and D-dimer: bedside tests to exclude pulmonary embolism.

STUDY OBJECTIVE: Less than 35% of patients suspected of having pulmonary embolism (PE) actually have PE. Safe bedside methods to exclude PE could save health-care resources and improve access to diagnostic testing for suspected PE. In patients with suspected PE, we sought to determine the sensitivity, specificity, and negative predictive value of (1) a steady-state end-tidal alveolar dead space fraction (AVDSf) of < 0.15, (2) a negative D-dimer result, and (3) the combination of a steady-state end-tidal AVDSf of < 0.15 and a negative D-dimer result. STUDY DESIGN: Prospective cohort study. SETTING: Tertiary-care center in Ottawa, Ontario, Canada. PATIENTS: Consecutive inpatients, outpatients, and emergency department patients with suspected PE referred to the Departments of Nuclear Medicine or Radiology for investigation of suspected PE. INTERVENTIONS AND MEASUREMENTS: All study patients had D-Dimer and alveolar dead space measurements prior to determining outcome (PE or no PE) with ventilation/perfusion scans and/or noninvasive leg vein imaging and/or pulmonary angiography. RESULTS: Two hundred forty-six eligible and consenting patients underwent diagnostic imaging that excluded PE in 163 patients, diagnosed PE in 49 patients, and was indeterminant in 34 patients. A negative D-dimer result excluded PE with a sensitivity of 83.0% (95% confidence interval [CI], 69.2 to 92.4%), a negative predictive value of 91.2% (95% CI, 83.4 to 96.1%), and a specificity of 57.6%. A steady-state end-tidal AVDSf of < 0.15 excluded PE with a sensitivity of 79.5% (95% CI, 63.5 to 90.7%), a negative predictive value of 90.7% (95% CI, 82.5 to 95.9%), and a specificity of 70.3%. The combination of a negative D-dimer result and a steady-state end-tidal AVDSf of < 0.15 excluded PE with a sensitivity of 97.8% (95% CI, 88.5 to 99.9%), a negative predictive value of 98.0% (95% CI, 89.4 to 99.9%), and a specificity of 38.0%. CONCLUSION: This simple combination of bedside tests may safely rule out PE without further diagnostic testing in large numbers of patients with suspected PE.

Second transplant for acute and chronic leukemia relapsing after first HLA-identical sibling transplant.

Treatment options for persons with leukemia relapsing after allogeneic transplantation are limited. We analyzed the outcome of 279 patients with acute and chronic leukemia, who relapsed after HLA-identical sibling transplantation and received a second allogeneic transplant. The influence of potential risk factors on treatment-related mortality (TRM), relapse, treatment failure (relapse or death) and overall survival after second transplantation were assessed using proportional-hazards regression. The cumulative incidences (95% confidence interval) of relapse and TRM at 5 years were 42 (36-48)% and 30 (24-36)%, respectively. The 5-year probabilities of both overall and leukemia-free survival were 28 (23-34)%. In multivariate analyses, risks of treatment failure and mortality were lower in younger patients (< or =20 years) and patients who relapsed after 6 months from first transplantation. Risks of relapse were lower in patients who relapsed after 6 months from first transplantation and in complete remission prior to second transplantation. Risks of relapse were higher after reduced-intensity conditioning regimens. Any potential advantage of using a different matched related donor for a second transplantation is not supported by these data. Although age, disease status and conditioning regimen are important, duration of remission after first transplantation appear to be the most important determinant of outcome.

Therapy-related acute myelogenous leukemia associated with 11q23 chromosomal abnormalities and topoisomerase II inhibitors: report of four additional cases and brief commentary.

We report 4 additional cases of therapy-related acute myelogenous leukemia (t-AML) with the translocation t(9;11)(p22q23). Chemotherapy for the primary malignancy (breast carcinoma in 2, non-Hodgkin's lymphoma in 2) included agents with topoisomerase II inhibitory activity (doxorubicin in 2; doxorubicin and etoposide in 1; doxorubicin, etoposide and mitoxantrone in 1) as well as alkylators. In agreement with previous reports, the leukemia was monoblastic (FAB M5 subtype) in all 4 patients, with only 1 having prior myelodysplasia, and the latency period from primary therapy was relatively short (24-48 months). All patients received potentially curative treatment for the leukemia which included allogeneic bone marrow transplantation in 3; however, all died (3 of t-AML and 1 of lymphoma). Therapy-related AML associated with exposure to agents with topoisomerase II inhibitory activity (epipodophyllotoxins and anthracyclines) is a distinct entity, the genetic basis and optimal treatment of which remain to be determined.

Treatment of acute promyelocytic leukemia in patients presenting at Vancouver General Hospital from 1983 to 1992.

Between 6/83 and 8/92, 23 of 361 patients (6.4%) presenting at Vancouver General Hospital with acute myelogenous leukemia had acute promyelocytic leukemia (APL). Treatment plan was: 1) induction with high-dose cytosine arabinoside and an intercalator; and 2) consolidation with allogeneic bone marrow transplantation (BMT) for those aged < or = 50 years with a sibling donor or repeat of induction for the the others. Complete remission (CR) was achieved in 20 patients (87%). Eleven patients in CR were eligible for allogeneic BMT; 4 were considered unsuitable, 2 refused, and 5 underwent this treatment--1 died of acute graft-versus-host disease, 1 relapsed and 3 are leukemia-free and well 1.6, 3.3 and 3.9 years after diagnosis. Fifteen patients did not undergo allogeneic BMT in CR; 4 received no further treatment and all died, 2 relapsed before consolidation therapy and both died, 1 underwent autologous BMT and died of complications, and 8 received consolidation treatment as planned--1 died of sepsis, 2 relapsed and 5 are leukemia-free and well 1.0, 3.8, 4.5, 4.9 and 8.5 years after diagnosis. The actuarial overall survival for all 23 patients was 38% (95% confidence interval [CI] 18-57%). The actuarial 2-year leukemia-free survival was 60% (95% CI 20-85%) for the 8 patients who underwent consolidation chemotherapy as planned and 53% (95% CI 68-86%) for the 5 patients who underwent allogeneic BMT in CR. These results suggest that patients with APL who are able to undergo consolidation chemotherapy have a relatively good prognosis and allogeneic BMT may reasonably be held in reserve for salvage therapy.

Transplant registries: guiding clinical decisions and improving outcomes.

About 50,000 hematopoietic stem cell transplantations are performed yearly, primarily for malignancies. Use of this therapy increased dramatically over the past 30 years due to its proven and potential efficacy in diverse diseases, better understanding of appropriate timing of transplantation and patient selection, and greater availability of allogeneic donors. The International Bone Marrow Transplant Registry (IBMTR) and the Autologous Blood and Marrow Transplant Registry (ABMTR) collect data on consecutive allogeneic and autologous transplants, respectively, in more than 400 participating centers worldwide. The IBMTR/ABMTR database contains information on more than 120,000 transplant recipients. Among 11,347 patients transplanted in 101 IBMTR/ABMTR research centers in North America during 1995-1997, 66% received autologous transplants, 24% related-donor transplants, and 10% unrelated-donor transplants. More than 90% of transplantations were for malignant disease, with more than half of these done in patients with advanced disease. Of the recipients, 70% were younger than 50 years. Posttransplant survivals varied substantially by disease, transplant type, recipient age, and disease status at transplantation. IBMTR/ABMTR data provide an important tool for assessing transplant use and outcome, identifying prognostic factors for transplant outcomes, evaluating new transplant therapies, comparing transplant and nontransplant therapies, evaluating late transplant complications, and planning prospective phase II and III clinical trials.

Similar outcomes using myeloablative vs reduced-intensity allogeneic transplant preparative regimens for AML or MDS.

Although reduced-intensity conditioning (RIC) and non-myeloablative (NMA)-conditioning regimens have been used for over a decade, their relative efficacy vs myeloablative (MA) approaches to allogeneic hematopoietic cell transplantation in patients with AML and myelodysplasia (MDS) is unknown. We compared disease status, donor, graft and recipient characteristics with outcomes of 3731 MA with 1448 RIC/NMA procedures performed at 217 centers between 1997 and 2004. The 5-year univariate probabilities and multivariate relative risk outcomes of relapse, TRM, disease-free survival (DFS) and OS are reported. Adjusted OS at 5 years was 34, 33 and 26% for MA, RIC and NMA transplants, respectively. NMA conditioning resulted in inferior DFS and OS, but there was no difference in DFS and OS between RIC and MA regimens. Late TRM negates early decreases in toxicity with RIC and NMA regimens. Our data suggest that higher regimen intensity may contribute to optimal survival in patients with AML/MDS, suggesting roles for both regimen intensity and graft vs leukemia in these diseases. Prospective studies comparing regimens are needed to confirm this finding and determine the optimal approach to patients who are eligible for either MA or RIC/NMA conditioning.

Rapamycin enriches for CD4(+) CD25(+) CD27(+) Foxp3(+) regulatory T cells in ex vivo-expanded CD25-enriched products from healthy donors and patients with multiple sclerosis.

BACKGROUND: CD4(+) CD25(bright+) regulatory T cells (Treg) can be expanded to clinical doses using CD3/CD28 Ab-coated beads plus IL-2. However, this method requires high purity of the starting population to prevent overgrowth by non-regulatory T cells. Rapamycin, an agent that inhibits T-cell proliferation but selectively spares Treg, may be a means to expand Treg from less pure CD25-enriched cells. METHODS: CD25-enriched cells were prepared by a single-step immunomagnetic-selection using anti-CD25 microbeads. The cells were activated with a single addition of anti-CD3/CD28 beads and expanded in ex vivo 15-5% HS and autologous CD4(+) CD25(-) feeder cells,+/-rapamycin (0.01-20 ng/mL). IL-2 was added on day 3. Cells were rested for 2 days in ex vivo 15-5% HS and tested for phenotype, intracellular Foxp3 protein and suppressor activity. RESULTS: In the absence of rapamycin, CD25-enriched fractions expanded >17 000-fold by 21 days. Although suppressor activity was detected to day 14, it declined significantly by 21 days as non-regulatory cells expanded. The addition of rapamycin inhibited expansion of non-regulatory T cells at doses > or =1 ng/mL while increasing suppressor activity and the percentage of CD4(+) CD25(+) CD27(+) Foxp3(+) cells. Rapamycin did not enrich for Foxp3(+) cells in expanded cultures of CD4(+) CD25(-) cells. Treg were also readily expanded in cultures of CD25-enriched cells obtained from patients with multiple sclerosis in the presence of rapamycin. DISCUSSION: The addition of 1-20 ng/mL rapamycin to CD25-enriched cultures increased the purity of cells with the phenotype and function of Treg. This approach may alleviate the need for rigorous enrichment of Treg prior to activation and expansion for potential clinical use.