Corina Herscovici

Cannabidiol for the Prevention of Graft-versus-Host-Disease after Allogeneic Hematopoietic Cell Transplantation: Results of a Phase II Study

Graft-versus-host-disease (GVHD) is a major obstacle to successful allogeneic hematopoietic cell transplantation (alloHCT). Cannabidiol (CBD), a nonpsychotropic ingredient of Cannabis sativa, possesses potent anti-inflammatory and immunosuppressive properties. We hypothesized that CBD may decrease GVHD incidence and severity after alloHCT. We conducted a phase II study. GVHD prophylaxis consisted of cyclosporine and a short course of methotrexate. Patients transplanted from an unrelated donor were given low-dose anti-T cell globulin. CBD 300 mg/day was given orally starting 7 days before transplantation until day 30. Forty-eight consecutive adult patients undergoing alloHCT were enrolled. Thirty-eight patients (79%) had acute leukemia or myelodysplastic syndrome and 35 patients (73%) were given myeloablative conditioning. The donor was either an HLA-identical sibling (n = 28), a 10/10 matched unrelated donor (n = 16), or a 1-antigen-mismatched unrelated donor (n = 4). The median follow-up was 16 months (range, 7 to 23). No grades 3 to 4 toxicities were attributed to CBD. None of the patients developed acute GVHD while consuming CBD. In an intention-to-treat analysis, we found that the cumulative incidence rates of grades II to IV and grades III to IV acute GVHD by day 100 were 12.1% and 5%, respectively. Compared with 101 historical control subjects given standard GVHD prophylaxis, the hazard ratio of developing grades II to IV acute GVHD among subjects treated with CBD plus standard GVHD prophylaxis was .3 (P = .0002). Rates of nonrelapse mortality at 100 days and at 1 year after transplantation were 8.6% and 13.4%, respectively. Among patients surviving more than 100 days, the cumulative incidences of moderate-to-severe chronic GVHD at 12 and 18 months were 20% and 33%, respectively. The combination of CBD with standard GVHD prophylaxis is a safe and promising strategy to reduce the incidence of acute GVHD. A randomized double-blind controlled study is warranted. (clinicaltrials.gov: NCT01385124).

High-dose cytarabine as salvage therapy for relapsed or refractory acute myeloid leukemia—is more better or more of the same?

Cytarabine is the backbone of most chemotherapeutic regimens for acute myeloid leukemia (AML), yet the optimal dose for salvage therapy of refractory or relapsed AML (RR‐AML) has not been established. Very high dose single‐agent cytarabine at 36 g/m2 (ARA‐36) was previously shown to be effective and tolerable in RR‐AML. In this retrospective analysis, we aim to describe the toxicity and efficacy of ARA‐36 as salvage therapy for patients with AML who are primary refractory to intensive daunorubicin‐containing induction or those relapsing after allogeneic stem cell transplant (alloSCT). Fifteen patients, median age 53 years, were included in the analysis. Six patients were treated for induction failure, one had resistant APL, and eight relapsed after alloSCT. Complete remission was achieved in 60% of patients. Surviving patients were followed for a median of 8.5 months. One‐year overall survival was 54% (95% CI 30%–86%), and relapse rate from remission (n = 9) was 56%. Grade III/IV pulmonary, infectious, ocular and gastrointestinal toxicities occurred in 26%, 20%, 20% and 20% of patients respectively. Salvage therapy with ARA‐36 regimen for RR‐AML has considerable efficacy with manageable toxicity in patients with induction failure or post‐transplant relapse. Overall survival in these high‐risk patients still remains poor. Copyright

Tailoring the GVHD prophylaxis regimen according to transplantation associated toxicities-Substituting the 3rd dose of methotrexate to mycophenolate mofetil.

We hypothesized that in patients with early post allogeneic transplantation toxicities, the omission of the 3rd dose of methotrexate with concomitant starting of MMF would favorably affect complications. We found a higher incidence of grade 2-4 acute GVHD in patients given two doses methotrexate and MMF (n=31) compared to those given three courses of methotrexate (n=70) (p=.004), while grade 3-4 was similar. Other transplantation outcomes, including overall regimen-related-toxicity, were comparable. We conclude that tailoring the GVHD prophylaxis regimen may decrease the early post transplantation complications, however this come at the extent of a higher incidence of non-severe acute GVHD.

Subcutaneous versus intravenous granulocyte colony stimulating factor for the treatment of neutropenia in hospitalized hemato-oncological patients: Randomized controlled trial

Intravenous (IV) granulocyte colony stimulating factor (G‐CSF) might be safer and more convenient than subcutaneous (SC) administration to hospitalized hemato‐oncological patients receiving chemotherapy. To compare IV vs. SC G‐CSF administration, we conducted a randomized, open‐label trial. We included inpatients receiving chemotherapy for acute myeloid leukemia, acute lymphoblastic leukemia, lymphoma or multiple myeloma, and allogeneic or autologous hematopoietic cell transplantation (HCT). Patients were randomized to 5 mcg/kg single daily dose of IV bolus versus SC filgrastim given for its clinical indications. Patients were crossed‐over to the alternate study arm on the subsequent chemotherapy course. The primary outcomes were time from initiation of filgrastim to recovery of stable neutrophil count of >500 cells/µL and a composite clinical outcome of infection or death assessed for the first course post‐randomization. The study was stopped on the second interim analysis. Of 120 patients randomized, 118 were evaluated in the first treatment course. The mean time to neutropenia resolution was longer with IV G‐CSF [7.9 days, 95% confidence interval (CI) 6.6–9.1] compared with SC G‐CSF (5.4 days, 95% CI 4.6–6.2), log‐rank P = 0.001. Longer neutropenia duration was observed in all patient subgroups, except for patients undergoing autologous HCT. There was no significant difference between groups in the occurrence of infection or death, but more deaths were observed with IV (4/57, 7%) versus SC (1/61, 1.6%) G‐CSF administration, P = 0.196. Similar results were observed when all 158 courses following cross‐over were analyzed. Patients reported similar pain and satisfaction scores in both groups. Bolus IV administration of G‐CSF results in longer neutropenia duration than SC administration, with no difference in clinical or quality‐of‐life measures. Am. J. Hematol. 89:243–248, 2014.

Elevation of CRP precedes clinical suspicion of bloodstream infections in patients undergoing hematopoietic cell transplantation

OBJECTIVES We aimed to examine whether C-reactive protein (CRP) elevation precedes the clinical signs and symptoms of infection among patients undergoing allogeneic hematopoietic cell transplantation (HCT). METHODS Prospective cohort of patients undergoing allogeneic HCT in whom daily blood samples for CRP were taken. In a nested case-control study, cases were defined as patients with clinically-significant bloodstream infection (BSI). Controls were defined as afebrile patients without infection, matched by age, time after transplantation and GVHD status. We calculated the mean difference (MD) between CRP 1 day before clinical suspicion of infection (day -1) and days -2 and -3 (deltaM1M2 and delta M1M3, respectively) and compared cases vs. controls. RESULTS From January 2010 to April 2012 we identified 46 cases of BSIs. The difference between the mean delta M1M3 and delta M1M2 in cases and controls were significantly higher in patients with BSI compared to controls (MD = 5.9, 95% CI 3.5-8.3, p < .001 and MD = 4.2 mg/dl, 95% CI 2.2-6.2, p < .001, respectively). In the overall cohort, sensitivity, specificity, positive and negative predictive values of a daily delta value >4 mg/dl were 52%, 98%, 66% and 98%, respectively. CONCLUSIONS A daily increase of CRP blood levels of >4 mg/dl in afebrile HCT recipients should trigger an evaluation for infection.

Cellular immune function monitoring after allogeneic haematopoietic cell transplantation: evaluation of a new assay.

Managing the patients immune system after haematopoietic cell transplantation (HCT) is a challenge, mainly in the unstable period immediately after the transplant. Currently there is no standardized non‐invasive diagnostic tool for the evaluation of immunological complications such as graft‐versus‐host disease (GVHD) and for managing the cellular immune function of the transplant recipient. The ImmuKnow assay for cellular immune function monitoring has been incorporated successfully into the clinical follow‐up routine of solid organ transplant recipients. This study aims to explore the relevance and potential contribution of immune monitoring using the assay in the setting of HCT. We found that ImmuKnow‐level measurement can distinguish between states of immune function quiescence and between events of acute GVHD. ImmuKnow levels were significantly higher in patients going through GVHD than the levels measured for the same patients during immunological stability. Moreover, we demonstrate a patient case where longitudinal monitoring using the ImmuKnow assay provided a trustworthy depiction of the patients cellular immune function post‐HCT. In conclusion, we provide evidence for the potential contribution of the ImmuKnow assay for longitudinal individualized cellular immune function monitoring of patients following HCT. Further studies are necessary in order to establish the optimal practice for utilizing the assay for this purpose.

Toxicity of autologous hematopoietic cell transplantation in patients with multiple myeloma – comparison between two different induction regimens

Induction therapy in patients with multiple myeloma has evolved from chemotherapy‐based to novel agents–based regimens. We compared autologous hematopoietic cell transplantation (HCT)‐associated toxicity in patients induced with VTD‐PACE (bortezomib, thalidomide, dexamethasone, cisplatinum, adriamycin, cyclophosphamide, and etoposide) to that of patients induced with novel agents–only therapy.