Kang Howson-Jan

Randomized Comparison of Gemcitabine, Dexamethasone, and Cisplatin Versus Dexamethasone, Cytarabine, and Cisplatin Chemotherapy Before Autologous Stem-Cell Transplantation for Relapsed and Refractory Aggressive Lymphomas: NCIC-CTG LY.12

PURPOSE For patients with relapsed or refractory aggressive lymphoma, we hypothesized that gemcitabine-based therapy before autologous stem-cell transplantation (ASCT) is as effective as and less toxic than standard treatment. PATIENTS AND METHODS We randomly assigned 619 patients with relapsed/refractory aggressive lymphoma to treatment with gemcitabine, dexamethasone, and cisplatin (GDP) or to dexamethasone, cytarabine, and cisplatin (DHAP). Patients with B-cell lymphoma also received rituximab. Responding patients proceeded to stem-cell collection and ASCT. Coprimary end points were response rate after two treatment cycles and transplantation rate. The noninferiority margin for the response rate to GDP relative to DHAP was set at 10%. Secondary end points included event-free and overall survival, treatment toxicity, and quality of life. RESULTS For the intention-to-treat population, the response rate with GDP was 45.2%; with DHAP the response rate was 44.0% (95% CI for difference, -9.0% to 6.7%), meeting protocol-defined criteria for noninferiority of GDP (P = .005). Similar results were obtained in a per-protocol analysis. The transplantation rates were 52.1% with GDP and 49.3% with DHAP (P = .44). At a median follow-up of 53 months, no differences were detected in event-free survival (HR, 0.99; stratified log-rank P = .95) or overall survival (HR, 1.03; P = .78) between GDP and DHAP. Treatment with GDP was associated with less toxicity (P < .001) and need for hospitalization (P < .001), and preserved quality of life (P = .04). CONCLUSION For patients with relapsed or refractory aggressive lymphoma, in comparison with DHAP, treatment with GDP is associated with a noninferior response rate, similar transplantation rate, event-free survival, and overall survival, less toxicity and hospitalization, and superior quality of life.

Results of a multicenter randomized phase II trial of thalidomide and prednisone maintenance therapy for multiple myeloma after autologous stem cell transplant.

We report a multicenter, randomized phase II trial conducted to assess the tolerability of combined thalidomide and prednisone maintenance in multiple myeloma. Eligibility required administration of melphalan (200 mg/m2) with blood stem cell support within 1 year of treatment onset and initiation of maintenance within 60 to 100 days after stem cell infusion. All patients received 50 mg of prednisone by mouth on alternate days and thalidomide at a starting dose of either 200 or 400 mg daily by mouth. The primary end point was the incidence of dropout or dose reduction due to treatment toxicity within 6 months. Sixty-seven patients were enrolled. Median follow-up is 36.8 months. The primary end point was reached by 31% of patients on the 200 mg of thalidomide arm and 64% of patients on the 400 mg of thalidomide arm. Allowing for dose reduction, 76% of patients assigned to the 200 mg of thalidomide arm and 41% of patients assigned to the 400 mg of thalidomide arm remained on any maintenance therapy 18 months after registration. Eighty-eight percent of all patients dose-reduced thalidomide and 72% of all patients dose-reduced prednisone within 2 years of beginning maintenance. The median progression-free survival post-transplant is 32.3 months, or 42.2 months from diagnosis. Only the 200 mg of thalidomide arm of this trial met our definition of a tolerable maintenance therapy, defined as no dose reductions or discontinuation due to toxicity in at least 65% of patients for a minimum of 6 months, thus establishing a dosing schedule for phase III trials.

Circulating hematopoietic stem cells serve as novel targets for in utero gene therapy

In utero gene therapy has been proposed as a method for permanent correction of somatic disorders that affect the hematopoietic system before disease initiation (1, 2). However, clinical trials using transplantation of allogenic fetal liver, bone marrow, or adult stem cells have been unsuccessful, largely due to the failure of sustained hematopoietic reconstitution in fetal recipients (3). Here, we reveal that retroviral transduction of unique repopulating stem cells found in the human fetal circulation is superior to full‐gestation cord blood or adult sources. In contrast to postnatal human stem cells, the fetal circulation is highly enriched for actively cycling blood stem cells, thereby forming the basis for enhanced transduction. Our findings indicate that active, transducible hematopoietic reconstituting cells are present in the circulation of the human fetus and that they represent novel target cells for future in utero gene therapy trials using autologous transplantation.

Acquired Factor VIII Inhibitor in a Patient with Chronic Myelogenous Leukemia Receiving Interferon-Alfa Therapy

OBJECTIVE: To report a case of an acquired factor VIII inhibitor associated with the use of interferon-alfa. CASE SUMMARY: A 58-year-old white man with newly diagnosed chronic myelogenous leukemia (CML) was initially treated with hydroxyurea. Interferon-alfa therapy was started six weeks later in order to enhance the response, with gradual reduction and eventual discontinuation of hydroxyurea. Interferon-alfa was continued for one year. Following bone marrow aspiration at one year, the patient developed significant bleeding and bruising at the site of extraction. His hemoglobin decreased from 11.3 to 9.3 g/dL and his activated partial thromboplastin time was elevated at 72 seconds. The factor VIII concentration was 0.02 units/mL; factor VIII inhibitor concentration was 58 Bethesda units. A diagnosis of an acquired factor VIII inhibitor was made, and the patient was treated with activated factor VII concentrates and prednisone. Interferon-alfa was discontinued, and the inhibitor subsequently disappeared over the next six weeks. The patient did not have any further bleeding problems. DISCUSSION: Acquired factor VIII inhibitors other than in patients with hemophilia are rare. To date, there are no reported cases of factor VIII inhibitors associated with CML. Moreover, the temporal association with interferon-alfa administration suggests a causal relationship. There are only two previous case reports suggesting interferon-alfa as a cause of factor VIII inhibitors. CONCLUSIONS: Induction of factor VIII inhibitors is a serious potential complication of therapy with interferon-alfa. We suggest that a diagnosis of an acquired factor VIII inhibitor be considered in patients who experience unexplained bleeding with interferon-alfa therapy.

Patient preferences for stopping tyrosine kinase inhibitors in chronic myeloid leukemia

BACKGROUND We used an interview-assisted survey of patients with chronic myeloid leukemia (cml) at a single tertiary care centre to explore patient reactions to and preferences for, and the risk-acceptability of, stopping tyrosine kinase inhibitor (tki) treatment. METHODS The study included patients with confirmed cml currently being treated with a tki. The survey was conducted by structured interview using a standard form. Patient preferences were explored in a case-based scenario using 0%-100% visual analog scales and 5-point Likert scales. Data were analyzed using proportions for dichotomous variables and medians and interquartile ranges for continuous variables. RESULTS Of 63 patients approached, 56 completed the survey. Participant responses suggest that the idea of stopping tki use is appealing to many patients if there is a chance of long-term stable disease and a high probability of response upon restarting a tki. Participants were more likely to stop their tki as the risk of relapse decreased. Participants reported loss of disease control and failure of disease to respond to treatment as important concerns if they chose to stop their tki. CONCLUSIONS Given the current 60% estimated rate of relapse after discontinuation of tki therapy, most patients with cml chose to continue with tki. However, at the lower relapse rates reported with second-generation tkis, participants were more undecided, demonstrating a basic understanding of risk. Contrary to our hypothesis, neither compliance nor occurrence of side effects significantly affected patient willingness to stop their tki.

Acute myeloid leukemia in a healthy hematopoietic stem cell donor following past exposure to a short course of G-CSF

Acute myeloid leukemia in a healthy hematopoietic stem cell donor following past exposure to a short course of G-CSF

Optimising parameters for peripheral blood leukapheresis after r-metHuG-CSF (filgrastim) and r-metHuSCF (ancestim) in patients with multiple myeloma: A temporal analysis of CD34+ absolute counts and subsets

Patients (n = 69) with multiple myeloma undergoing peripheral blood stem cell collection (PBSC) were treated with cyclophosphamide and a combination of recombinant methionyl human granulocyte colony-stimulating factor (r-metHuG-CSF, filgrastim) and recombinant methionyl human stem cell factor (r-metHuSCF, ancestim). The objectives of this study were to determine: (1) The proportion of patients reaching a target yield of ⩾5 × 106 CD34+ cells/kg in one or two successive large-volume (20 liter) leukapheresis procedures; (2) the optimal collection time for leukapheresis; (3) mobilization kinetics of CD34+ subsets in response to G-CSF/SCF. All patients were mobilized with cyclophosphamide (2.5 g/m2) on day 0 followed by filgrastim (10 μg/kg) plus ancestim (20 μg/kg) commencing day 1 and continuing to day 11 or 12. Of the 65 evaluable patients, 57 were considered not heavily pretreated and 96.5% obtained a target of ⩾5 × 106/kg in one collection. The median CD34+ cells/kg was 39.5 × 106 (range: 5.2–221.2 × 106). Subset analysis demonstrated the number of CD38−, CD33−, and CD133+ peaked at day 11; and CD34+, CD90+ cells peaked at day 10. The optimum day for leukapheresis was determined to be day 11. The median absolute peripheral blood CD34+ cell numbers on day 11 was 665 × 106/l (range: 76–1481 × 106/l). Eight of the 10 heavily pretreated patients were evaluable: three achieved the target dose in one leukapheresis (37.5%) and three (37.5%) achieved the target dose with two leukaphereses. Use of this mobilization strategy allowed the collection of high numbers of CD34+ cells and early progenitors and the ability to predictably schedule leukapheresis.

Predictors of unsuccessful mobilization with granulocyte colony-stimulating factor alone in patients undergoing autologous hematopoietic stem cell transplantation

Mobilization of hematopoietic stem cells is achieved with hematopoietic growth factors with or without chemotherapy or other agents. Although studies comparing granulocyte colony‐stimulating factor (G‐CSF) alone to combined regimens demonstrate an increase in stem cell yield in the latter, mobilization with G‐CSF alone is still effective and has been widely practiced. We conducted a retrospective cohort study of consecutive patients at our institution who underwent at least one mobilization attempt with G‐CSF between January 2000 and December 2008 to identify the proportion of patients failing one or more mobilization attempts and the potential predictors of mobilization failure with this regime. Out of 293 patients, 251 (86.6%) were successfully mobilized and 244 (83.6%) underwent hematopoietic stem cell transplantation. Median yield was 3.55 × 106 CD34+ cells/kg. On univariate analysis, mobilization success was influenced by degree of previous treatment and underlying diagnosis (P < 0.001 each) but not by age (P = 0.114), sex (P = 0.860), or radiotherapy (P = 0.454). A diagnosis of non‐Hodgkins lymphoma (NHL) and number of previous chemotherapy regimens were predictors of failure on multivariate analysis. CD34+ yield was influenced by diagnosis and previous chemotherapy (P < 0.001 each). Mobilization with G‐CSF alone yields adequate collections for most patients; however, heavily pretreated NHL patients with one failed attempt had high rates of remobilization failure and should be considered for alternative regimens. J. Clin. Apheresis 28:285–292, 2013.

Posterior reversible encephalopathy syndrome in a patient with multiple myeloma treated with thalidomide.

Posterior reversible encephalopathy syndrome (PRES) is a clinical-radiologic syndrome presenting with headache, mental status changes and visual disturbances accompanied by typical fi ndings on magnetic resonance imaging (MRI). Th e majority of reported cases have been linked to hypertension or pre-eclampsia; however, a signifi cant number of cases have also been associated with immunosuppressive agents or chemotherapy. We report the second documented case of PRES in association with thalidomide treatment, an agent that has been used in maintenance therapy post-autologous hematopoietic stem cell transplant and in combination fi rstline therapy for multiple myeloma. A 49-year-old woman presented with an episode of involuntary right leg shaking initially lasting 10 min. Upon arrival to the emergency department via the emergency medical services, she had a second episode of involuntary right leg movement lasting approximately 45 min. Intermittent, involuntary leg shaking continued for the fi2 h of her hospital stay and then evolved into a witnessed generalized tonic – clonic seizure with incontinence, loss of consciousness and a post-ictal period. Her seizure was terminated with the administration of lorazepam. Physical examination of the cardiac, respiratory and abdominal systems was unremarkable. Neurologic examination revealed normal cranial nerves including full extraocular movements and visual fi elds. She had slightly decreased power diff usely to the right upper extremity, but full power in her other limbs, and refl exes were 3 throughout. Sensory, cerebellar and gait testing were all normal. Orientation, naming, repetition and memory were all intact. She was normotensive. Fluid-attenuated inversion recovery (FLAIR) sequence MRI demonstrated multiple foci of T2 hyperintensity in the occipital and posterior parietal lobes extending into the medial and superior parietal regions bilaterally, as well as involvement of the deep paracentral white matter. Diff usion weighted imaging was normal (Figure 1). Th e patient ’ s clinical presentation, accompanied by these typical radiologic fi ndings, was considered to be most consistent with PRES. Th e patient ’ s medical history was signifi cant for a T10 plasmacytoma requiring surgical resection, laminectomy and stabilization, 2 years previously. She had received radiotherapy to the area and undergone an autologous hematopoietic stem cell transplant following dexamethasone induction for her concurrent lambda light chain multiple myeloma, performed 1 year prior to presentation. She had been started on maintenance thalidomide following her transplant, and, at the time of her seizure, had been on thalidomide 200 mg daily for approximately 11 months. At presentation, her other medications also included pregabalin, hydromorphone and monthly pamidronate infusions. Within hours of admission to hospital, she developed a fever which was treated with empiric antibiotic therapy, initially cefotaxime and azithromycin, subsequently changed to meropenem. A vesicular rash then developed over her truncal region and was treated with acyclovir. Polymerase chain reaction (PCR) testing of vesicular fl uid later confi rmed the presence of varicella zoster virus. Blood cultures taken prior to the initiation of antibiotic and antiviral therapy were subsequently found to be negative, and a chest radiograph was unremarkable. Lumbar puncture was not done at the time because of the presence of the zoster rash over the lumbosacral area. Th e patient completed a 7-day course of antibiotics and acyclovir and was discharged home with an additional 10 days of oral acyclovir. She was not given steroid therapy. A diff use rash was noted following initiation of dilantin therapy, and she was switched to valproic acid because of concern regarding a dilantin allergic reaction. She was discharged on valproic acid 500 mg twice daily. She did not develop any further seizures or other neurologic events, and her level of consciousness and cognition remained normal during the course of her stay in hospital and thereafter. Th e patient ’ s seizures were not felt to be related to herpes simplex encephalitis (HSE) as they were not typical in origin or character for HSE and were relatively easily controlled. Th e imaging pattern was typical of PRES rather than viral encephalitis, and she did not develop any other neurologic sequelae suggestive of encephalitis. Her myeloma was in

Erratum to “Filgrastim-Stimulated Bone Marrow Compared with Filgrastim-Mobilized Peripheral Blood in Myeloablative Sibling Allografting for Patients with Hematologic Malignancies: A Randomized Canadian Blood and Marrow Transplant Group Study” [Biol Blood Marrow Transplant 2016;22:1410-1415]

Stephen Couban, Mahmoud Aljurf, Sylvie Lachance, Irwin Walker, Cynthia Toze, Morel Rubinger, Jeffrey H. Lipton, Stephanie J. Lee, Jeff Szer, Richard Doocey, Ian D. Lewis, Lothar Huebsch, Kang Howson-Jan, Michel Lalancette, Fahad Almohareb, Nadeem Chaudhri, Sabine Ivison, Raewyn Broady, Megan Levings, Diane Fairclough, Gerald Devins, David Szwajcer, Ronan Foley, Clayton Smith, Tony Panzarella, Holly Kerr, Amina Kariminia, Kirk R. Schultz