Autologous Hematopoietic Stem Cell Transplantation for Liver Transplant Recipients With Recurrent Primary Sclerosing Cholangitis: A Pilot Study.

BACKGROUND: Primary sclerosing cholangitis (PSC) is an indication for liver transplantation, but recurrence after liver transplantation is associated with poor outcomes often requiring repeat transplantation. We investigated whether autologous hematopoietic stem cell transplantation (aHSCT) could be used to stop progression of recurrent PSC and promote operational tolerance. METHODS: Twelve patients with recurrent PSC were fully evaluated and 5 were selected for aHSCT. Autologous hematopoietic stem cells were collected, purified by CD34 immunomagnetic selection, and cryopreserved. Immunoablation using busulfan, cyclophosphamide, and rabbit antithymocyte globulin was followed by aHSCT. The primary endpoint of the study was the establishment of operational tolerance defined as lack of biochemical, histologic, and clinical evidence of rejection while off immunosuppression at 2 y post-aHSCT. RESULTS: Two of the 5 patients achieved operational tolerance with no clinical or histologic evidence of PSC progression or allorejection. A third patient developed sinusoidal obstruction syndrome following aHSCT requiring repeat liver transplantation but has no evidence of PSC recurrence while on sirolimus monotherapy now >3 y after aHSCT. A fourth patient was weaned off immunosuppression but died 212 d after aHSCT from pericardial constriction. A fifth patient died from multiorgan failure. Immunosuppression-free allograft acceptance was associated with deletion of T-cell clones, loss of autoantibodies, and increases in regulatory T cells, transitional B cells, and programmed cell death protein-1 expressing CD8+ T cells in the 2 long-term survivors. CONCLUSIONS: Although operational tolerance occurred following aHSCT, the high morbidity and mortality observed render this specific protocol unsuitable for clinical adoption.

Weekly carfilzomib plus cyclophosphamide and dexamethasone in the treatment of relapsed/refractory multiple myeloma: Final results from the MCRN-003/MYX.1 single arm phase II trial.

The MCRN-003/CCTGMYX.1 is a single arm phase II trial of weekly carfilzomib, cyclophosphamide and dexamethasone (wKCd), exploring a convenient immunomodulator (IMiD)-free regimen in relapsed myeloma. Weekly carfilzomib (20/70 mg/m2 ), dexamethasone 40 mg and cyclophosphamide 300 mg/m2 was delivered over 28-day cycles. The primary endpoint was overall response after four cycles. Secondary endpoints included toxicity, response depth, PFS and OS. Exploratory endpoints included the impact of cytogenetics, prior therapy exposure and serum free light chain (sFLC) escape; 76 patients were accrued. The ORR was 85% (68% ≥very good partial response [VGPR] and 29% ≥complete response [CR]). The median OS and PFS were 27 and 17 months respectively. High-risk cytogenetics conferred a worse ORR (75% vs. 97%, p = .013) and median OS (18 months vs. NR, p = .002) with a trend toward a worse median PFS (14 vs. 22 months, p = .06). Prior proteasome inhibitor (PI) or lenalidomide did not influence OS or PFS. The sFLC was noted in 15% of patients with a median PFS of 17 months when included as a progression event. The most common ≥ grade 3 non-hematologic adverse events were infectious (40%), vascular (17%) and cardiac (15%). The wKCD is a safe and effective regimen in relapse, especially for patients ineligible for lenalidomide-based therapies.

Drug-induced Thrombotic Microangiopathy with Concurrent Proteasome Inhibitor Use in the Treatment of Multiple Myeloma: A Case Series and Review of the Literature.

Thrombotic microangiopathy (TMA) is a life-threatening clinical syndrome characterized by hemolytic anemia, thrombocytopenia, and microvascular thrombosis, resulting in ischemia and organ damage. Multiple myeloma (MM) is a neoplasm arising from clonal plasma cells within the bone marrow. The treatment frequently includes multi-agent immunochemotherapy, often with the use of proteasome inhibitors (PIs) such as bortezomib, carfilzomib, or ixazomib. There are increasing reports of TMA in association with PI exposure. This review summarizes the epidemiology, pathogenesis, and diagnosis of PI-related drug-induced TMA. We will outline the definition and diagnosis of TMA and explore an important cause of hemolysis in patients with MM: drug-induced TMA after PI exposure, an increasingly recognized therapeutic complication. This will be emphasized through the description of 3 novel cases of TMA. These illustrative cases occurred after treatment with high-dose weekly carfilzomib, cyclophosphamide, and dexamethasone as part of the MCRN003/MYX1 phase II clinical trial (NCT02597062) in relapsed MM.

Randomized study of continuous high-dose lenalidomide, sequential azacitidine and lenalidomide, or azacitidine in persons 65 years and over with newly-diagnosed acute myeloid leukemia.

Therapy of acute myeloid leukemia in older persons is associated with poor outcomes because of intolerance to intensive therapy, resistant disease and co-morbidities. This multi-center, randomized, open-label, phase II trial compared safety and efficacy of three therapeutic strategies in patients 65 years or over with newly-diagnosed acute myeloid leukemia: 1) continuous high-dose lenalidomide (n=15); 2) sequential azacitidine and lenalidomide (n=39); and 3) azacitidine only (n=34). The efficacy end point was 1-year survival. Median age was 76 years (range 66-87 years). Thirteen subjects (15%) had prior myelodysplastic syndrome and 41 (47%) had adverse cytogenetics. One-year survival was 21% [95% confidence interval (CI): 0, 43%] with high-dose lenalidomide, 44% (95%CI: 28, 60%) with sequential azacitidine and lenalidomide, and 52% (95%CI: 35, 70%) with azacitidine only. Lenalidomide at a continuous high-dose schedule was poorly-tolerated resulting in a high rate of early therapy discontinuations. Hazard of death in the first four months was greatest in subjects receiving continuous high-dose lenalidomide; hazards of death thereafter were similar. These data do not favor use of continuous high-dose lenalidomide or sequential azacitidine and lenalidomide over the conventional dose and schedule of azacitidine only in patients aged 65 years or over with newly-diagnosed acute myeloid leukemia. (clinicaltrials.gov identifier: 01358734).

Overall survival in lower IPSS risk MDS by receipt of iron chelation therapy, adjusting for patient-related factors and measuring from time of first red blood cell transfusion dependence: an MDS-CAN analysis.

Analyses suggest iron overload in red blood cell (RBC) transfusion-dependent (TD) patients with myleodysplastic syndrome (MDS) portends inferior overall survival (OS) that is attenuated by iron chelation therapy (ICT) but may be biassed by unbalanced patient-related factors. The Canadian MDS Registry prospectively measures frailty, comorbidity and disability. We analysed OS by receipt of ICT, adjusting for these patient-related factors. TD International Prognostic Scoring System (IPSS) low and intermediate-1 risk MDS, at RBC TD, were included. Predictive factors for OS were determined. A matched pair analysis considering age, revised IPSS, TD severity, time from MDS diagnosis to TD, and receipt of disease-modifying agents was conducted. Of 239 patients, 83 received ICT; frailty, comorbidity and disability did not differ from non-ICT patients. Median OS from TD was superior in ICT patients (5·2 vs. 2·1 years; P < 0·0001). By multivariate analysis, not receiving ICT independently predicted inferior OS, (hazard ratio for death 2·0, P = 0·03). In matched pair analysis, OS remained superior for ICT patients (P = 0·02). In this prospective, non-randomized analysis, receiving ICT was associated with superior OS in lower IPSS risk MDS, adjusting for age, frailty, comorbidity, disability, revised IPSS, TD severity, time to TD and receiving disease-modifying agents. This provides additional evidence that ICT may confer clinical benefit.

Patient-related factors independently impact overall survival in patients with myelodysplastic syndromes: an MDS-CAN prospective study.

UNLABELLED: Little is known about the effects of frailty, disability and physical functioning on the clinical outcomes for myelodysplastic syndromes (MDS). We investigated the predictive value of these factors on overall survival (OS) in 445 consecutive patients with MDS and chronic monomyelocytic leukaemia (CMML) enrolled in a multi-centre prospective national registry. Frailty, comorbidity, instrumental activities of daily living, disability, quality of life, fatigue and physical performance measures were evaluated at baseline and were added as covariates to conventional MDS-related factors as predictors of OS in Cox proportional hazards models. The median age was 73 years, and 79% had revised International Prognostic Scoring System (IPSS-R) risk scores of intermediate or lower. Frailty correlated only modestly with comorbidity. OS was significantly shorter for patients with higher frailty and comorbidity scores, any disability, impaired grip strength and timed chair stand tests. By multivariate analysis, the age-adjusted IPSS-R, frailty (Hazard ratio 2·7 (95% confidence interval [CI] 1·7-4·2), P < 0·0001) and Charlson comorbidity score (Hazard ratio 1·8 (95% CI 1·1-2·8), P = 0·01) were independently prognostic of OS. Incorporation of frailty and comorbidity scores improved risk stratification of the IPSS-R by 30% and 5%, respectively. These data demonstrate for the first time, the importance of considering frailty in prognostic models and a potential target for therapeutic intervention in optimizing clinical outcomes in older MDS patients. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02537990.

Effects of a pharmacy-driven perisplenectomy vaccination program on vaccination rates and adherence to guidelines.

BACKGROUND: Overwhelming postsplenectomy infection is a serious potential outcome for patients who have undergone resection of the spleen and is associated with a high mortality rate. The most common bacterial causes are the encapsulated organisms Streptococcus pneumoniae, Neisseria meningitidis, and Hemophilus influenzae type B, all of which are vaccine-preventable. Current guidelines recommend vaccination against these 3 bacteria, but adherence to these guidelines is less than ideal. In 2007, a "perisplenectomy vaccination kit" was introduced at the authors' institution to improve compliance with immunization guidelines by making the vaccines and necessary information for patients and providers more readily available. OBJECTIVE: To evaluate and compare vaccination rates for patients who underwent splenectomy before and after introduction of the perisplenectomy vaccination kit and, secondarily, to identify any characteristics unique to those who did not receive appropriate perisplenectomy vaccinations. METHODS: In this observational study, performed at the QEII Health Sciences Centre of Capital Health in Halifax, Nova Scotia, data were reviewed for patients who underwent splenectomy between 2008 and 2011. Vaccination rates and other descriptive statistics were calculated and compared with data for a 3-year period before implementation of the program. RESULTS: Vaccination rates in the 3-year period following implementation of the perisplenectomy vaccination kit were 100% against S. pneumoniae, 97% against N. meningitidis, and 93% against H. influenzae type B. The corresponding rates in the 3 years before introduction of the kit were 91%, 75%, and 68%, respectively. No characteristics predicting inadequate immunization were identified in univariate or multivariate analysis. CONCLUSION: Introduction of a pharmacy-driven perisplenectomy vaccination kit program improved rates of appropriate vaccination for patients who underwent splenectomy.

CONTEXTE: L'infection fulminante post-splénectomie, une complication potentielle sérieuse chez les patients ayant subi une ablation de la rate, présente un taux de mortalité élevé. Les causes bactériennes les plus fréquentes de cette infection sont les bactéries encapsulées Streptococcus pneumoniae, Neisseria meningitidis et Haemophilus influenzae de type b, qui peuvent toutes être prévenues par un vaccin. Les lignes directrices actuelles recommandent une vaccination contre ces trois espèces de bactéries, mais le respect de ces lignes directrices est loin d'être idéal. En 2007, une « trousse de vaccination périsplénectomie ¼ a été adoptée dans l'établissement des auteurs. Cette trousse avait pour but d'améliorer le degré de conformité aux lignes directrices sur l'immunisation en facilitant l'accès aux vaccins et aux renseignements nécessaires pour les patients et les professionnels de la santé. OBJECTIF: Déterminer quels étaient les taux de vaccination des patients ayant subi une splénectomie avant et après la mise en place de la « trousse de vaccination périsplénectomie ¼, puis comparer ces valeurs; et identifier toute caractéristique propre à ceux qui n'ont pas reçu les vaccins nécessaires durant la période entourant la splénectomie. MÉTHODES: Dans cette étude observationnelle menée au QEII Health Sciences Centre de Capital Health à Halifax (Nouvelle-Écosse), on a procédé à l'analyse des données concernant les patients ayant subi une splénectomie entre 2008 et 2011. Les taux de vaccination ainsi que d'autres statistiques descriptives ont été calculés et comparés à des données d'une période de trois ans avant la mise en œuvre du programme d'utilisation de la « trousse de vaccination périsplénectomie ¼. RÉSULTATS: Les taux de vaccination de la période de trois ans qui a suivi la mise en œuvre de la « trousse de vaccination périsplénectomie ¼ étaient de 100 % pour S. pneumoniae, 97 % pour N. meningitidis et 93 % pour H. influenzae de type b. Les taux correspondants des trois années précédant cette mise en œuvre étaient respectivement de 91 %, 75 % et 68 %. Aucun prédicteur d'une immunisation insuffisante n'a été cerné par l'analyse univariée ou multivariée. CONCLUSION: L'implantation d'un programme de « trousse de vaccination périsplénectomie ¼ mené par les pharmaciens a permis d'accroître les taux d'administration des vaccins qui sont indiqués chez les patients ayant subi une splénectomie. [Traduction par l'éditeur].

A case of congenital TTP presenting with microganiopathy in adulthood.

BACKGROUND: Congenital thrombotic thrombocytopenic purpura (TTP), also known as Upshaw-Schulman Syndrome is a rare inherited deficiency of ADAMTS13. Unlike the more common acquired TTP which is characterized by an acquired inhibitor of ADAMTS13, patients with congenital TTP have an absolute deficiency of ADAMTS13 without an inhibitor. Congenital TTP generally presents in infancy with repeat episodes of acute hemolysis and evidence of microangiopathy, these episodes are usually triggered by illness or physiological stress. Congenital TTP can be effectively treated with plasma infusion either during acute episodes or on a prophylactic schedule to prevent episodes. CASE PRESENTATION: We present a case of a 25 year old Caucasian woman with no know family history of hematological disorders with congenital TTP. She presented with episodes of hemolysis since infancy, but without clear evidence of microangiopathy until the age of 25. At presentation to our center the patient was documented to have thrombocytopenia, elevated creatinine, and schistocytes. She was initially treated with plasma infusion at a rate of 60 ml/hr continuously for a 24 hr period with resolution of her thrombocytopenia and hemolysis. At the time of writing this article she is maintained on a prophylactic schedule of biweekly plasma infusions at 10 mg/kg and is maintaining a normal platelet count with no evidence of hemolysis. CONCLUSION: Congenital TTP is a rare condition, and the above case is atypical as the patient did not present with clear evidence of microangiopathy until adulthood. Although this a rare condition it is important for physicians to be aware of as it, especially the possibility of atypical presentations, as the condition is potentially fatal and effective treatment exists.

Acute promyelocytic leukaemia is characterized by stable incidence and improved survival that is restricted to patients managed in leukaemia referral centres: a pan-Canadian epidemiological study.

Timely diagnosis and care are major determinants of the outcome in acute promyelocytic leukaemia (APL), a malignancy whose incidence may be increasing. The Canadian Cancer Registry (CCR) and health system represent valuable settings to study APL epidemiology. We analysed the CCR, which contains data on all Canadians with APL. To provide clinical information lacking in the CCR, we obtained data from five leukaemia referral centres during a similar time period. Between 1993 and 2007, there were 399 APL in Canada. Age-standardized incidence was 0·083/100,000 and was stable over time. The early death (ED) rate was 21·8% (10·6% in patients <50 years old and 35·5% for those aged >50 years), with no improvement over time. Five-year overall survival (OS) was 54·6% (73·3% in patients <50 years; 29·1% older patients). In the referral cohort, 131 patients were diagnosed between 1999 and 2010. ED was 14·6% and 2-year OS was 76·5%. Within this cohort, ED and OS improved over time, although advanced patient age remained an adverse determinant of OS. In Canada, APL incidence is unexpectedly low and temporally stable. ED was higher than reported in clinical trials, but similar to reports from other registries. In contrast, ED was lower in referral centres and improved with time.

Treatment of older patients with acute myeloid leukemia (AML): a Canadian consensus.

Patients over age 60 comprise the majority of those diagnosed with acute myeloid leukemia (AML), but treatment approaches in this population are variable, with many uncertainties and controversies. Our group conducted a literature review to summarize the latest information and to develop a consensus document with practical treatment recommendations. We addressed five key questions: selection criteria for patients to receive intensive induction chemotherapy; optimal induction and post-remission regimens; allogeneic hematopoietic stem cell transplantation (HSCT); treatment of patients not suitable for induction chemotherapy; and treatment of patients with prior hematological disorders or therapy-related AML. Relevant literature was identified through a PubMed search of publications from 1991 to 2012. Key findings included the recognition that cytogenetics and molecular markers are major biologic determinants of treatment outcomes in the older population, both during induction therapy and following HSCT. Although disease-specific and patient-specific risk factors for poor outcomes are more common in the older population, age is not in itself sufficient grounds for withholding established treatments, including induction and consolidation chemotherapy. The role of HSCT and use of hypomethylating agents are discussed. Finally, suggested treatment algorithms are outlined, based on these recommendations.

Optimizing patient selection for myeloablative allogeneic hematopoietic cell transplantation in chronic myeloid leukemia in chronic phase.

Outstanding results have been obtained in the treatment of chronic myeloid leukemia (CML) with first-line imatinib therapy. However, approximately 35% of patients will not obtain long-term benefit with this approach. Allogeneic hematopoietic stem cell transplantation (HCT) is a valuable second- and third-line therapy for appropriately selected patients. To identify useful prognostic indicators of transplantation outcome in postimatinib therapeutic interventions, we investigated the role of the HCT comorbidity index (HCT-CI) together with levels of C-reactive protein (CRP) before HCT in 271 patients who underwent myeloablative HCT for CML in first chronic phase. Multivariate analysis showed both an HCT-CI score higher than 0 and CRP levels higher than 9 mg/L independently predict inferior survival and increased nonrelapse mortality at 100 days after HCT. CML patients without comorbidities (HCT-CI score 0) with normal CRP levels (0-9 mg/L) may therefore be candidates for early allogeneic HCT after failing imatinib.

Bilateral renal sinus myelolipomas.

Adrenal myelolipomas are benign neoplasms consisting of hematopoietic cellular elements and adipose tissue. They are uncommon, found in 0.4% to 1% of the population at autopsy. Extra-adrenal myelolipomas (EM) are extremely rare with fewer than 50 cases reported. We describe the first case of bilateral EM of the renal sinus. They are difficult to diagnose on imaging alone when arising in this location and biopsies may not yield a definitive answer. Management options include both conservative and surgical approaches depending upon the certainty of the diagnosis, progression of the patient's symptoms and evidence of growth.

A long-term durable remission with high-dose therapy and autologous stem cell transplant for stage IVB HIV-associated Hodgkins disease.

A 44-year-old man with relapsed HIV-associated stage IV nodular sclerosing Hodgkin's disease underwent high-dose therapy with autologous stem cell transplantation. The transplant was uncomplicated and the patient remains in complete remission at 59 months. Autologous stem cell transplantation is safe in HIV patients and can achieve long-term durable remissions in Hodgkin's disease.

Outcome of hematopoietic stem cell transplant recipients admitted to the intensive care unit.

Stem cell transplantation (SCT) is associated with complications that may necessitate intensive care unit (ICU) admission. The outcome for SCT patients requiring ICU admission has been reported to be poor. We describe the outcome of consecutive SCT patients admitted to the ICU at a single center. The study was a retrospective review of all patients at the Queen Elizabeth II Health Sciences Center who received an SCT between 1992 and 2001 and were subsequently admitted to the ICU. The primary outcome was overall survival at 12 months after ICU admission. There were 440 SCTs in the study period; 38 of these patients were admitted to the ICU on 42 separate occasions. The primary indication for ICU admission was respiratory failure. The probability of survival at 12 months was 21.6% (95% CI, 8.4%-34.9%). On multivariate analysis, the only statistically significant variable associated with decreased 12-month survival was vasopressor use. The probability of survival for patients receiving vasopressor support was 5% (95% CI, 0%-14.5%) at 30 days and 0% at 12 months, whereas the probability of survival for patients not receiving vasopressor support was 76.5% (95% CI, 56.3%-96.6%) at 30 days and 45.8% (95% CI, 21.5%-69.9%) at 12 months. In this 10-year review of consecutive SCT recipients requiring ICU admission, we found that the outcome of SCT patients requiring ICU admission may not be as poor as previously reported. However, SCT recipients requiring vasopressor support had very poor outcomes. These findings will be important in deciding which SCT patients may benefit from ICU admission and care.