Prognostic Index for Critically Ill Allogeneic Transplantation Patients.

Outcomes of intensive care for allogeneic hematopoietic stem cell transplantation (Allo-SCT) patients remain poor. Better selection of critically ill Allo-SCT patients for intensive care may alleviate costs to the patients, families, and the health care system. We aimed to develop a prognostic index tailored for critically ill Allo-SCT patients as traditional instruments are of limited value in this setting. Six hundred fifty-six Allo-SCT patients admitted to intensive care unit (ICU) at MD Anderson Cancer Center between 2001 and 2010 were divided into training and test sets. Of the 3 multivariable regression models built to predict hospital mortality in the training set, the model with the largest area under receiver operating curve (AUC) in the test set was selected as the prognostic index for intensive care after allogeneic hematopoietic stem cell transplantation (PICAT). The parameters included in the regression model with the highest AUC (.81) were time to ICU from hospital admission, lactate dehydrogenase, bilirubin, albumin, reason for ICU admission, prothrombin time-international normalized ratio, conditioning intensity, age, and comorbidity score. AUC for hospital mortality of PICAT (.80) was significantly larger than that of Acute Physiology and Chronic Health Evaluation (APACHE) (.61) and Sequential Organ Failure Assessment (SOFA) (.72) in all patients. Hospital mortality and median overall survival of patients with PICAT scores of 0 to 2 (n = 141), >2 to 4 (n = 242), and >4 (n = 182) were 34%, 69%, and 91%; and 7.59, .67, and .30 months, respectively. PICAT has good calibration and accuracy in predicting mortality for Allo-SCT patients requiring intensive care. Its AUC was significantly higher than APACHE II and SOFA scores and is also associated with overall survival.

Intensive care outcomes in adult hematopoietic stem cell transplantation patients.

Although outcomes of intensive care for patients undergoing hematopoietic stem cell transplantation (HSCT) have improved in the last two decades, the short-term mortality still remains above 50% among allogeneic HSCT patients. Better selection of HSCT patients for intensive care, and consequently reduction of non-beneficial care, may reduce financial costs and alleviate patient suffering. We reviewed the studies on intensive care outcomes of patients undergoing HSCT published since 2000. The risk factors for intensive care unit (ICU) admission identified in this report were primarily patient and transplant related: HSCT type (autologous vs allogeneic), conditioning intensity, HLA mismatch, and graft-versus-host disease (GVHD). At the same time, most of the factors associated with ICU outcomes reported were related to the patients' functional status upon development of critical illness and interventions in ICU. Among the many possible interventions, the initiation of mechanical ventilation was the most consistently reported factor affecting ICU survival. As a consequence, our current ability to assess the benefit or futility of intensive care is limited. Until better ICU or hospital mortality prediction models are available, based on the available evidence, we recommend practitioners to base their ICU admission decisions on: Patient pre-transplant comorbidities, underlying disease status, GVHD diagnosis/grade, and patients' functional status at the time of critical illness.

Optimal Threshold and Time of Absolute Lymphocyte Count Assessment for Outcome Prediction after Bone Marrow Transplantation.

The recovery pace of absolute lymphocyte count (ALC) is prognostic after hematopoietic stem cell transplantation. Previous studies have evaluated a wide range of ALC cutoffs and time points for predicting outcomes. We aimed to determine the optimal ALC value for outcome prediction after bone marrow transplantation (BMT). A total of 518 patients who underwent BMT for acute leukemia or myelodysplastic syndrome between 1999 and 2010 were divided into a training set and a test set to assess the prognostic value of ALC on days 30, 60, 90, 120, 180, as well as the first post-transplantation day of an ALC of 100, 200, 300, 400, 500, and 1000/µL. In the training set, the best predictor of overall survival (OS), relapse-free survival (RFS), and nonrelapse mortality (NRM) was ALC on day 60. In the entire patient cohort, multivariable analyses demonstrated significantly better OS, RFS, and NRM and lower incidence of graft-versus-host disease (GVHD) in patients with an ALC >300/µL on day 60 post-BMT, both including and excluding patients who developed GVHD before day 60. Among the patient-, disease-, and transplant-related factors assessed, only busulfan-based conditioning was significantly associated with higher ALC values on day 60 in both cohorts. The optimal ALC cutoff for predicting outcomes after BMT is 300/µL on day 60 post-transplantation.

"No donor"? Consider a haploidentical transplant.

Haploidentical stem cell transplantation (HaploSCT) is an attractive option for patients requiring a hematopoietic stem cell transplant who do not have an HLA-matched donor, because it is cheaper, can be performed faster, and may extend transplantation to virtually all patients in need. Significant advances have been made in the recent decade with dramatic improvement in treatment outcomes. Historically, overcoming the HLA-incompatibility barrier has been a significant limitation to the expansion of this form of transplant. While ex vivo T-cell depletion effectively prevented the development of acute GVHD, it was associated with a higher treatment-related mortality, in excess of 40% in some series, due to a significant delay in recovery of the adaptive immune system. Newer methods have successfully maintained the memory T cells in the graft and/or selectively depleted alloreactive T cells, and are associated with improved treatment outcomes. Post-transplant cyclophosphamide for GVHD prevention has proven very effective in controlling GVHD with lower incidence of infectious complications and treatment-related mortality-as low as 7% at 1 year-and has become the new standard in how this transplant is performed. Here, we reviewed the current experience with this approach and various other strategies employed to control alloreactivity in this setting, including selective depletion of T cells from the graft, as well as we discuss post-transplantation therapy to prevent disease relapse and improve immunologic reconstitution.

Hematopoietic cell transplantation-specific comorbidity index predicts inpatient mortality and survival in patients who received allogeneic transplantation admitted to the intensive care unit.

PURPOSE: To investigate the prognostic value of the Hematopoietic Cell Transplantation-Specific Comorbidity Index (HCT-CI) in patients who received transplantation admitted to the intensive care unit (ICU). PATIENTS AND METHODS: We investigated the association of HCT-CI with inpatient mortality and overall survival (OS) among 377 patients who were admitted to the ICU within 100 days of allogeneic stem-cell transplantation (ASCT) at our institution. HCT-CI scores were collapsed into four groups and were evaluated in univariate and multivariate analyses using logistic regression and Cox proportional hazards models. RESULTS: The most common pretransplantation comorbidities were pulmonary and cardiac diseases, and respiratory failure was the primary reason for ICU admission. We observed a strong trend for higher inpatient mortality and shorter OS among patients with HCT-CI values ≥ 2 compared with patients with values of 0 to 1 in all patient subsets studied. Multivariate analysis showed that patients with HCT-CI values ≥ 2 had significantly higher inpatient mortality than patients with values of 0 to 1 and that HCT-CI values ≥ 4 were significantly associated with shorter OS compared with values of 0 to 1 (hazard ratio, 1.74; 95% CI, 1.23 to 2.47). The factors associated with lower inpatient mortality were ICU admission during the ASCT conditioning phase or the use of reduced-intensity conditioning regimens. The overall inpatient mortality rate was 64%, and the 1-year OS rate was 15%. Among patients with HCT-CI scores of 0 to 1, 2, 3, and ≥ 4, the 1-year OS rates were 22%, 17%, 18%, and 9%, respectively. CONCLUSION: HCT-CI is a valuable predictor of mortality and survival in critically ill patients after ASCT.

Ex vivo T cell-depleted versus unmodified allografts in patients with acute myeloid leukemia in first complete remission.

This study was conducted to retrospectively compare the clinical outcomes after transplantation of T cell-depleted (TCD) and unmodified allografts in patients with acute myeloid leukemia (AML) in first complete remission (CR1). Patients received TCD grafts at Memorial Sloan-Kettering Cancer Center (MSKCC, N = 115) between 2001 and 2010 using the following preparative regimens: hyperfractionated total body irradiation (HFTBI)+thiotepa+fludarabine; HFTBI+thiotepa+cyclophosphamide; or i.v. busulfan+melphalan+fludarabine. TCD was performed by 1 of 2 immunomagnetic CD34(+) cell selection methods for peripheral blood grafts or by soybean lectin agglutination followed by sheep red blood cell-rosette depletion for bone marrow grafts. No additional graft-versus-host disease (GVHD) prophylaxis was administered. Patients received unmodified grafts at M.D. Anderson Cancer Center (MDACC, N = 181) after conditioning with busulfan+fludarabine and GVHD prophylaxis with tacrolimus+mini-methotrexate. Patients with unrelated or human leukocyte antigen-mismatched donors received anti-thymocyte globulin (ATG) at both centers, with some recipients of matched related donor TCD transplants also receiving ATG, depending upon the preparative regimen. TCD graft recipients were more likely to be older, receive a mismatched transplant, and have peripheral blood used as the graft source. The incidences rates of grades 2 to 4 acute GVHD and chronic GVHD were significantly lower in the TCD graft group (5% versus 18%, and 13% versus 53%). Three-year relapse-free and overall survival rates were 58% and 57%, respectively, in recipients of TCD grafts, and 60% and 66% in recipients of unmodified grafts (P = not significant). Survival and relapse-free survival are similar after TCD and conventional transplants from related/unrelated donors in patients with AML in CR1, but TCD significantly reduces GVHD.

Fifty years of melphalan use in hematopoietic stem cell transplantation.

Melphalan remains the most widely used agent in preparative regimens for hematopoietic stem cell transplantation (SCT). From its initial discovery more than 50 years ago, it has been gradually incorporated in the conditioning regimens for both autologous and allogeneic transplantations because of its myeloablative properties and broad antitumor effects as a DNA alkylating agent. Melphalan remains the mainstay conditioning for multiple myeloma and lymphomas, and it has been used successfully in preparative regimens of a variety of other hematological and nonhematological malignancies. The addition of newer agents to conditioning, such as bortezomib or lenalidomide for myeloma or clofarabine for myeloid malignancies, may improve antitumor effects for transplantation, whereas melphalan in combination with alemtuzumab may represent a backbone for future cellular therapy because of reliable engraftment and low toxicity profile. This review summarizes the development and the current use of this remarkable drug in hematopoietic SCT.

Strategies in haploidentical stem cell transplantation in adults.

UNLABELLED: Haploidentical related donors are alternative stem cell sources for patients without human leukocyte antigen (HLA)-matched related or unrelated donors. Immediate access to the donor, availability for patients with rare haplotypes, ease of stem cell procurement, and lack of a requirement for a physical cord blood bank or an extensive HLA database render this type of hematopoietic stem cell transplantation particularly attractive despite the high histoincompatibility barrier between the recipient and the haploidentical graft. In this review, we answer the following questions: 1) What are the current transplant strategies used to overcome the histoincompatibility barrier in haploidentical stem cell transplantation and their clinical results? 2) How should we choose the donor when there is more than one available haploidentical donor? 3) How does transplantation from haploidentical donors compare to that from umbilical cord blood? CONFLICT OF INTEREST: None declared.

Improved early outcomes using a T cell replete graft compared with T cell depleted haploidentical hematopoietic stem cell transplantation.

Haploidentical stem cell transplantation (SCT) has been generally performed using a T cell depleted (TCD) graft; however, a high rate of nonrelapse mortality (NRM) has been reported, particularly in adult patients. We hypothesized that using a T cell replete (TCR) graft followed by effective posttransplantation immunosuppressive therapy would reduce NRM and improve outcomes. We analyzed 65 consecutive adult patients with hematologic malignancies who received TCR (N = 32) or TCD (N = 33) haploidentical transplants. All patients received a preparative regimen consisting of melphalan, fludarabine, and thiotepa. The TCR group received posttransplantation treatment with cyclophosphamide (Cy), tacrolimus (Tac), and mycophenolate mofetil (MMF). Patients with TCD received antithymocyte globulin followed by infusion of CD34+ selected cells with no posttransplantation immunosuppression. The majority of patients in each group had active disease at the time of transplantation. Outcomes are reported for the TCR and TCD recipients, respectively. Engraftment was achieved in 94% versus 81% (P = NS). NRM at 1 year was 16% versus 42% (P = .02). Actuarial overall survival (OS) and progression-free survival (PFS) rates at 1 year posttransplantation were 64% versus 30% (P = .02) and 50% versus 21% (P = .02). The cumulative incidence of grade II-IV acute graft-versus-host disease (aGVHD) was 20% versus 11% (P = .20), and chronic GVHD (cGVHD) 7% versus 18% (P = .03). Improved reconstitution of T cell subsets and a lower rate of infection were observed in the TCR group. These results indicate that a TCR graft followed by effective control of GVHD posttransplantation may lower NRM and improve survival after haploidentical SCT.

Outcome of patients with relapsed/refractory acquired immune deficiency syndrome-related lymphoma diagnosed 1999-2008 and treated with curative intent in the AIDS Malignancy Consortium.

No comparative studies exist for relapsed/refractory (rel/rfr) acquired immune deficiency syndrome (AIDS)-related lymphoma (ARL). To determine practices over the last decade and to assess the outcomes of salvage chemotherapy with curative intent and autologous stem cell transplant (ASCT), we retrospectively evaluated treatment outcomes in patients with rel/rfr ARL who were treated in 13 national AIDS Malignancy Consortium (AMC) sites between 1999 and 2008 (n = 88). The most commonly used second-line therapies were ICE (ifosfamide/carboplatin/etoposide, n = 34), dose adjusted EPOCH (etoposide/prednisone/vincristine/cyclophosphamide/doxorubicin, n = 17) and ESHAP (etoposide/methylprednisolone/cytarabine/cisplatin, n = 11). The odds of achieving a response were lower for those with non-Hodgkin lymphoma (NHL) than for those with HL and for those with primary refractory disease than for those with relapse. Overall survival (OS) was significantly longer for those with relapsed disease compared to those with refractory disease and for those with non-Burkitt NHL compared to those with Burkitt. OS was longer in patients who underwent ASCT compared to those who did not (1-year OS: 63.2% vs. 37.2%). However, among 32 patients (36%) who achieved a complete or partial response (CR/PR) after second-line therapy, 1-year OS was not different between the two groups (87.5% for ASCT vs. 81.8% for non-ASCT). Long-term survival in some patients with rel/rfr ARL may be possible without transplant, although transplant remains the standard of care for chemotherapy sensitive disease.

Vitamin D receptor upregulation in alloreactive human T cells.

Vitamin D deficiency is adversely associated with diseases characterized by inflammation. The combination of the high incidence of vitamin D deficiency in patients undergoing allogeneic stem cell transplants (SCT) and the potential role of vitamin D deficiency in influencing graft-versus-host disease led us to further characterize the expression of VDR on alloreactive T cells. We hypothesized that vitamin D receptor expression may directly regulate alloreactive T cell responses. To overcome existing limitations in measuring VDR in bulk cellular populations, we developed a flow cytometric assay to measure cytoplasmic VDR in human T cells. Upon stimulation, VDR was expressed extremely early and exhibited sustained upregulation with chronic stimulation. VDR expression was also coupled to cytokine production, proliferation, and ERK1/2 phosphorylation. In addition, VDR exhibited a maturation stage-specific pattern of expression, with greatest expression on cells known to mediate GVHD, naïve and early memory T cells. Alloreactive T cells upregulated VDR, whereas the nonreactive T cells did not. Finally, repletion of vitamin D in vitro was sufficient to significantly reduce alloreactive T cell responses. These data suggest that vitamin D effects on T cells may be important in reducing graft versus host disease (GVHD) in the allogeneic stem cell transplant setting.

Progress in haploidentical stem cell transplantation.

Haploidentical stem cell transplantation is an attractive form of transplantation because of the immediate donor availability, ease of stem cell procurement, and the possibility to further collect donor cells for cellular therapy. Historically, maintaining T cells in the graft has been associated with very high rates of graft-versus-host-disease (GVHD), whereas T cell-depleted haploidentical transplantation has been limited by a higher incidence of graft rejection and nonrelapse mortality related to infectious complications as a result of delayed immune reconstitution posttransplantation. Recent approaches have attempted to eliminate the alloreactive T cells to prevent GVHD posttransplantation. Administration of high-dose cyclophosphamide early posttransplantation in combination with tacrolimus and mycophenolate mofetil has produced engraftment and GVHD rates similar to HLA-matched sibling transplants, suggesting that the most important barriers against successful haploidentical transplantation can be overcome. Future directions should focus on optimizing conditioning regimens for different diseases and prevention of disease relapse posttransplantation.

Primary CNS lymphoma in HIV positive and negative patients: comparison of clinical characteristics, outcome and prognostic factors.

Primary central nervous system lymphoma (PCNSL) accounts for approximately 4% of all primary brain tumors and has a poor prognosis in both immunocompetent as well as in immunocompromised patients. We conducted a retrospective analysis to examine the clinical characteristics and prognostic factors in HIV-negative and HIV-positive patients with PCNSL and to assess the effect of highly active antiretroviral therapy (HAART) therapy on the outcome of HIV-positive patients. Patients diagnosed with PCNSL between 1999 and 2008 at our institution were divided into two groups based on their HIV status. Their demographic and clinical characteristics were compared using the chi-square test. Kaplan-Meier survival curves were constructed employing the univariate log-rank test. Multivariate analyses of survival were performed by Cox proportional hazards models incorporating the prognostic factors identified in the univariate log rank test. Forty-one HIV-positive patients and 45 HIV-negative patients were identified. HIV-positive patients were younger, more likely to present with seizures and elevated serum LDH levels. There were significant differences in complete remission (CR) rates (P = 0.010) and overall survival (OS) (P = 0.034) in favor of the HIV-negative group. In the HIV-positive group, OS was better in patients with KPS > 70 and patients who received HAART, but remained inferior to that in the HIV-negative patients. HIV-positive patients had a worse prognosis compared to HIV-negative patients despite similar clinical characteristics. Better performance status (KPS > 70) and treatment with HAART conferred better OS in HIV-positive patients.

Primary ocular adnexal mucosa-associated lymphoid tissue lymphoma (MALT): single institution experience in a large cohort of patients.

Extranodal marginal zone B-cell lymphoma is the most common orbital tumour. We conducted a retrospective analysis to examine: (i) the impact of initial presentation and staging on outcome and (ii) response to various treatment modalities and the effect of the latter on recurrence. Ninety patients with primary ocular adnexal marginal zone lymphoma (POAML) diagnosed at our institution between 1984 and 2009 were studied. POAML was associated with monoclonal gammopathy (13%) at presentation. Most POAML patients (86%) presented with Ann-Arbor stage I disease. Radiotherapy led to excellent local control, but relapses occurred in 18% of Ann-Arbor stage I patients during a median follow-up of 5 years. Local relapses, including secondary central nervous system (CNS) involvement, were observed in patients receiving radiation doses <30·6 Gy. No differences in relapse rate and survival were observed between patients who did or did not undergo staging bone marrow biopsy. Ann-Arbor stage II-IV disease and high lactate dehydrogenase levels were associated with shorter freedom from progression. In conclusion, POAML is an indolent lymphoma with continuous risk for relapse. Radiation doses of at least 30·6 Gy should be given in Ann-Arbor stage I disease, since lower doses may be more frequently associated with relapses, including CNS relapses.

Timing of adjuvant and neoadjuvant therapy in colorectal cancers.

Surgery remains the only curative therapy for colorectal cancer (CRC); however, several studies have proved that adjuvant chemotherapy improves the curative rate. A growing body of evidence indicates that significant deviations from recommended treatment plans are frequent. Patients may experience delays in the administration of adjuvant chemotherapy that can reduce its survival benefit. To date, few studies have examined factors associated with the timing of adjuvant chemotherapy or have described the effects of delayed therapy on overall survival. In this review, we discuss the extent and predictors of delay in administration of adjuvant chemotherapy as well as the relationship between timing and outcomes in CRC.

Treatment of iron deficiency anemia associated with gastrointestinal tract diseases.

The gastrointestinal (GI) tract is a common site of bleeding that may lead to iron deficiency anemia (IDA). Treatment of IDA depends on severity and acuity of patients' signs and symptoms. While red blood cell transfusions may be required in hemodynamically unstable patients, transfusions should be avoided in chronically anemic patients due to their potential side effects and cost. Iron studies need to be performed after episodes of GI bleeding and stores need to be replenished before anemia develops. Oral iron preparations are efficacious but poorly tolerated due to non-absorbed iron-mediated GI side effects. However, oral iron dose may be reduced with no effect on its efficacy while decreasing side effects and patient discontinuation rates. Parenteral iron therapy replenishes iron stores quicker and is better tolerated than oral therapy. Serious hypersensitive reactions are very rare with new intravenous preparations. While data on worsening of inflammatory bowel disease (IBD) activity by oral iron therapy are not conclusive, parenteral iron therapy still seems to be advantageous in the treatment of IDA in patients with IBD, because oral iron may not be sufficient to overcome the chronic blood loss and GI side effects of oral iron which may mimic IBD exacerbation. Finally, we believe the choice of oral vs parenteral iron therapy in patients with IBD should primarily depend on acuity and severity of patients' signs and symptoms.

Molecular basis and management of gastrointestinal stromal tumors.

Molecularly targeted agents have dramatically impacted the management of several cancers. Targeting KIT has led to a new treatment paradigm in gastrointestinal stromal tumors (GISTs). KIT is a cell surface receptor with tyrosine kinases that, upon binding of its ligand, stem cell factor, activates various signaling pathways. Imatinib and sunitinib, both tyrosine kinase inhibitors directed to KIT, were approved for first- and second-line treatment of metastatic and unresectable GISTs. In this article, we will review the molecular pathogenesis of GISTs followed by a discussion of imatinib and sunitinib's role in the treatment of GISTs. Finally, we will introduce novel therapeutic options for imatinib- and sunitinib-resistant GISTs.

Lycopene in cancer prevention and treatment.

Dietary intake of lycopene is inversely associated with the risk of many cancers. Preclinical studies show that lycopene has potent in vitro and in vivo antitumor effects, suggesting potential preventive and therapeutic roles for the compound. However, clinical trials with lycopene have only recently been started, and available clinical data preclude firm conclusions with regard to its use in cancer prevention and treatment. Further mechanistic studies and randomized controlled clinical intervention trials with lycopene involving cancer patients are warranted.

The clinical spectrum of catastrophic antiphospholipid syndrome in the absence and presence of lupus.

OBJECTIVE: To compare the clinical spectrum of patients with primary catastrophic antiphospholipid syndrome (P-CAPS) to those with systemic lupus erythematosus-associated CAPS (SLE-CAPS). METHODS: We used the Internet-based CAPS Registry to compare the demographic, clinical, and laboratory characteristics of 127 P-CAPS patients to 103 SLE-CAPS patients. In a logistic regression analysis, we also determined the poor prognostic factors for mortality. RESULTS: At the time of CAPS diagnosis, compared to patients with P-CAPS, those with SLE-CAPS were more likely to be female and younger; have cerebral and pancreatic involvement; receive corticosteroids and cyclophosphamide; demonstrate a lower prevalence of high titer (> or = 80 U) IgG anticardiolipin antibody; and have a higher risk for mortality after adjusting for age, sex, organ involvement, and treatment. Based on a logistic regression analysis, cyclophosphamide use was associated with increased mortality in P-CAPS but improved survival in SLE-CAPS patients. CONCLUSION: SLE is a poor prognostic factor in patients with CAPS and cyclophosphamide may be beneficial in those with SLE-CAPS.