Ian Gabriel

Allogeneic Hematopoietic Cell Transplantation for Patients With Mycosis Fungoides and Sézary Syndrome: A Retrospective Analysis of the Lymphoma Working Party of the European Group for Blood and Marrow Transplantation

PURPOSE To analyze the outcome of allogeneic transplantation for mycosis fungoides and Sézary syndrome (MF/SS) in terms of nonrelapse mortality (NRM), relapse/progression (REL), progression-free survival (PFS), and overall survival (OS) and to identify factors associated with the outcome. PATIENT AND METHODS Sixty patients with MF (n = 36) and SS (n = 24) who received a first allogeneic hematopoietic cell transplantation (HCT) from a matched related (mRD; n = 45) or unrelated donor (mUD; n = 15) between 1997 and 2007 and who were registered in the European Group for Blood and Marrow Transplantation database were analyzed: 37 men and 23 women, median age 46.5 years (range, 22 to 66 years). Forty-four patients had TNM stage IV, and 40 patients were at advanced phase at transplantation. Forty-four patients received reduced-intensity conditioning (RIC) regimens, and 25 underwent T-cell depletion (TCD). RESULTS Allogeneic transplantation in MF/SS offers an estimated OS of 66% at 1 year and 54% at 3 years, primarily driven by donor type, disease phase, and type of conditioning. RIC decreased NRM (relative risk [RR] = 4.7; P = .008) without increasing REL, leading to a higher OS (RR = 2.8; P = .03). Advanced-phase disease increases REL (RR = 3.0; P = .03) and reduces PFS (RR = 4.4; P = .002) and OS (RR = 3.5; P = .023). Recipients of mRD allogeneic HCT had better PFS (RR = 2.7; P = .006) and OS (RR = 4.0; P = .001) than their mUD counterparts. The risk of REL increases with TCD (RR = 3.2; P = .005). Some patients who experience relapse can successfully undergo rescue treatment with donor lymphocyte infusions. CONCLUSION Allogeneic transplantation is a valid therapeutic alternative for high-risk patients with advanced-stage MF/SS. Our data also suggest the existence of a clinically relevant graft-versus-lymphoma effect in MF/SS.

Pleural effusions in patients with chronic myeloid leukaemia treated with dasatinib may have an immune‐mediated pathogenesis

patients with an expected better safety profile than that of the regimen used in our study. The ongoing UK AML 16 Trial, which evaluates a regimen combining low-dose cytarabine (20 mg/12 h, days 1–10) and low dose GO (5 mg, day 1) in patients not considered fit for intensive treatment, will better define the clinical benefit resulting from such a strategy (http:// www.download.bham.ac.uk/bctu/AML16/Trial/AML16%20 Protocol%20V5%20May%202006.pdf).

Comparable survival between HIV+ and HIV- non-Hodgkin and Hodgkin lymphoma patients undergoing autologous peripheral blood stem cell transplantation.

Autologous stem cell transplantation (ASCT) has been successfully used in HIV-related lymphoma (HIV-Ly) patients on highly active antiretroviral therapy. We report the first comparative analysis between HIV-Ly and a matched cohort of HIV(-) lymphoma patients. This retrospective European Group for Blood and Marrow Transplantation study included 53 patients (66% non-Hodgkin and 34% Hodgkin lymphoma) within each cohort. Both groups were comparable except for the higher proportion of males, mixed-cellularity Hodgkin lymphoma and patients receiving granulocyte colony-stimulating factor before engraftment and a smaller proportion receiving total body irradiation-based conditioning within the HIV-Ly cohort. Incidence of relapse, overall survival, and progression-free survival were similar in both cohorts. A higher nonrelapse mortality within the first year after ASCT was observed in the HIV-Ly group (8% vs 2%), predominantly because of early bacterial infections, although this was not statistically significant and did not influence survival. Thus, within the highly active antiretroviral therapy era, HIV patients should be considered for ASCT according to the same criteria adopted for HIV(-) lymphoma patients.

Autologous Stem-Cell Transplantation in Patients With HIV-Related Lymphoma

PURPOSE Peripheral-blood autologous stem-cell transplantation (ASCT) in patients with HIV-related lymphoma (HIV-Ly) has been reported as a safe and useful procedure. Herein we report the European Group for Blood and Marrow Transplantation experience on patients with HIV-Ly undergoing ASCT. PATIENTS AND METHODS This was a retrospective, multicentric, registry-based analysis. RESULTS Since 1999, 68 patients from 20 institutions (median age, 41 years; range, 29 to 62 years) were included, diagnosed with non-Hodgkins lymphoma (NHL; n = 50) or Hodgkins lymphoma (n = 18). At the time of ASCT, 16 patients were in first complete remission (CR1); 44 patients were in CR more than 1, partial remission, or chemotherapy-sensitive relapse (chemo-S); and eight patients had chemotherapy-resistant disease. The median number of CD34(+) cells infused was 4.5 x 10(6)/kg (range, 1.6 to 21.2 x 10(6)/kg). Median time to neutrophil and platelet engraftment were 11 days (range, 8 to 36 days) and 14 days (range, 6 to 455 days), respectively, with a cumulative incidence (CI) at 1 year of 95.6% and 87%, respectively. CI of nonrelapse mortality (NRM) was 7.5% at 12 months after ASCT, mainly because of bacterial infections. CI of relapse was 30.4% at 24 months, statistically related with not being in CR at ASCT (relative risk [RR] = 3.6), NHL histology other than diffuse large B-cell lymphoma (RR = 3.4), and use of more than two previous treatment lines (RR = 3). At a median follow-up of 32 months (range, 2 to 81 months), progression-free survival (PFS) was 56%. Patients not in CR or with refractory disease at ASCT had poorer PFS (RR = 2.4 and 4.8, respectively). CONCLUSION Similarly to HIV-negative patients with lymphoma, ASCT is a useful treatment for patients with HIV-Ly and is associated with low NRM, mainly when performed in early stages and chemo-S disease.

Repeated vaccination is required to optimize seroprotection against H1N1 in the immunocompromised host.

Background In 2009 the declaration by the World Health Organization of a global pandemic of influenza-H1N1 virus led to a vaccination campaign to ensure protection for immunocompromised patients. The goal of this study was to determine the efficacy of the 2009 H1N1 vaccine in patients with hematologic malignancies. Design and Methods We evaluated humoral and cellular immune responses to 2009 H1N1 vaccine in 97 adults with hematologic malignancies and compared these responses with those in 25 adult controls. Patients received two injections of vaccine 21 days apart and the controls received one dose. Antibody titers were measured using a hemagglutination-inhibition assay on days 0, 21 and 49 after injection of the first dose. Cellular immune responses to H1N1 were determined on days 0 and 49. Results By day 21 post-vaccination, protective antibody titers of 1:32 or more were seen in 100% of controls compared to 39% of patients with B-cell malignancies (P<0.001), 46% of allogeneic stem cell transplant recipients (P<0.001) and 85% of patients with chronic myeloid leukemia (P=0.086). After a second dose, seroprotection rates increased to 68%, (P=0.008), 73%, (P=0.031), and 95% (P=0.5) in patients with B-cell malignancies, after allogeneic stem cell transplantation and with chronic myeloid leukemia, respectively. On the other hand, T-cell responses to H1N1 vaccine were not significantly different between patients and controls. Conclusions These data demonstrate the efficacy of H1N1 vaccine in most patients with hematologic malignancies and support the recommendation for the administration of two doses of vaccine in immunocompromised patients. These results may contribute towards the development of evidence-based guidelines for influenza vaccination in such patients in the future.

Investigation of the effect of marathon running on leucocyte counts of subjects of different ethnic origins: relevance to the aetiology of ethnic neutropenia.

Healthy subjects of African ancestry, including Afro‐Caribbeans, have been observed to have lower total white cell counts and neutrophil counts than healthy Caucasian subjects. The cause of this ethnic neutropenia is unclear. We have previously found no evidence that increased margination of neutrophils is responsible. In this study, we have investigated mobilization of neutrophils from the bone marrow granulocyte reserve by endurance exercise. We investigated subjects of different ethnic origins before and after they had competed in a marathon race. Before the race, the neutrophil counts of Africans/Afro‐Caribbeans were significantly lower than those of Caucasians (means 2.49 and 3.21 × 109/l respectively; P = 0.043). After the race, the difference was greater, as was the degree of significance (means 10.21 and 12.33 respectively; P = 0.017). The percentage increment was almost identical whereas the absolute increment was considerably less, although of marginal statistical significance (increment 7.72 and 9.12 × 109/l respectively; P = 0.10). Similar changes were observed in the monocyte count. Before the race, the difference in the means was of marginal statistical significance (0.35 and 0.41 × 109/l respectively; P = 0.105), whereas after the race the difference was greater and was highly significant (means 0.75 and 1.05 × 109/l respectively; P = 0.001). These observations support the results of our earlier study, both of which suggested that ethnic neutropenia is likely to result from a diminished bone marrow reserve rather than being consequent on altered distribution of neutrophils within the blood stream.

KIR2DS1 genotype predicts for complete cytogenetic response and survival in newly diagnosed chronic myeloid leukemia patients treated with imatinib.

Natural killer (NK) cells are expanded in chronic myeloid leukemia (CML) patients on tyrosine kinase inhibitors (TKI) and exert cytotoxicity. The inherited repertoire of killer immunoglobulin-like receptors (KIR) may influence response to TKI. We investigated the impact of KIR-genotype on outcome in 166 chronic phase CML patients on first-line imatinib treatment. We validated our findings in an independent patient group. On multivariate analysis, KIR2DS1 genotype (RR=1.51, P=0.03) and Sokal risk score (low-risk RR=1, intermediate-risk RR=1.53, P=0.04, high-risk RR=1.69, P=0.034) were the only independent predictors for failure to achieve complete cytogenetic response (CCyR). Furthermore, KIR2DS1 was the only factor predicting shorter progression-free (PFS) (RR=3.1, P=0.03) and overall survival (OS) (RR=2.6, P=0.04). The association between KIR2DS1 and CCyR, PFS and OS was validated by KIR genotyping in 174 CML patients on first-line imatinib in the UK multi-center SPIRIT-1 trial; in this cohort, KIR2DS1(+) patients had significantly lower 2-year probabilities of achieving CCyR (76.9 vs 87.9%, P=0.003), PFS (85.3 vs 98.1%, P=0.007) and OS (94.4 vs 100%, P=0.015) than KIR2DS1(−) patients. The impact of KIR2DS1 on CCyR was greatest when the ligand for the corresponding inhibitory receptor, KIR2DL1, was absent (P=0.00006). Our data suggest a novel role for KIR-HLA immunogenetics in CML patients on TKI.

Tyrosine kinase inhibitors impair B-cell immune responses in CML through off-target inhibition of kinases important for cell signaling

Tyrosine kinase inhibitors (TKIs) have significant off-target multikinase inhibitory effects. We aimed to study the impact of TKIs on the in vivo B-cell response to vaccination. Cellular and humoral responses to influenza and pneumococcal vaccines were evaluated in 51 chronic phase chronic myeloid leukemia (CML) patients on imatinib, or second-line dasatinib and nilotinib, and 24 controls. Following vaccination, CML patients on TKI had significant impairment of IgM humoral response to pneumococcus compared with controls (IgM titer 79.0 vs 200 U/mL, P = .0006), associated with significantly lower frequencies of peripheral blood IgM memory B cells. To elucidate whether CML itself or treatment with TKI was responsible for the impaired humoral response, we assessed memory B-cell subsets in paired samples collected before and after imatinib therapy. Treatment with imatinib was associated with significant reductions in IgM memory B cells. In vitro coincubation of B cells with plasma from CML patients on TKI or with imatinib, dasatinib, or nilotinib induced significant and dose-dependent inhibition of Brutons tyrosine kinase and indirectly its downstream substrate, phospholipase-C-γ2, both important in B-cell signaling and survival. These data indicate that TKIs, through off-target inhibition of kinases important in B-cell signaling, reduce memory B-cell frequencies and induce significant impairment of B-cell responses in CML.

Plerixafor for Autologous Peripheral Blood Stem Cell Mobilization in Patients Previously Treated with Fludarabine or Lenalidomide

Fludarabine and lenalidomide are essential drugs in the front-line treatment of non-Hodgkin lymphoma (NHL) and multiple myeloma (MM), respectively. Data suggests that fludarabine and lenalidomide therapy may have a deleterious effect on stem cell mobilization. In the European compassionate use program, 48 patients (median age 57 years) previously treated with fludarabine (median 5 cycles; range: 1-7 cycles) were given plerixafor plus granulocyte colony-stimulating factor (G-CSF) for remobilization following a primary mobilization attempt. The overall median number of CD34+ cells collected was 2.3 × 10(6)/kg (range: 0.3-13.4). The minimum required number of CD34+ cells (≥2.0 × 10(6)/kg) was collected from 58% of patients in a median of 2 days. Thirty-five patients (median age = 57 years) previously treated with lenalidomide (median 5 cycles; range: 1-10 cycles) were given plerixafor plus G-CSF for remobilization. The overall median number of CD34+ cells collected was 3.4 × 10(6)/kg (range: 1.1-14.8). The minimum required number of CD34+ cells (≥2.0 × 10(6) per kg) was collected from 69% of patients in a median of 2 days. In conclusion, salvage mobilization with plerixafor plus G-CSF is successful in the majority of patients with MM previously treated with lenalidomide. In fludarabine-exposed patients, only 58% of patients will achieve successful salvage mobilization with plerixafor plus G-CSF, suggesting the need for novel mobilization regimens algorithms in this subgroup of patients.

Interaction between KIR3DS1 and HLA-Bw4 predicts for progression-free survival after autologous stem cell transplantation in patients with multiple myeloma.

Natural killer (NK) cells exert antimyeloma cytotoxicity. The balance between inhibition and activation of NK-cells played by the inherited repertoire of killer immunoglobulin-like receptor (KIR) genes therefore may influence prognosis. One hundred eighty-two patients with multiple myeloma (MM) were analyzed for KIR repertoire. Multivariate analysis showed that progression-free survival (PFS) after autologous stem cell transplantation (ASCT) was significantly shorter for patients who are KIR3DS1(+) (P = .01). This was most evident for patients in complete or partial remission (good risk; GR) at ASCT. The relative risk (RR) of progression or death for patients with KIR3DS1(+) compared with KIR3DS1(-) was 1.9 (95% CI, 1.3-3.1; P = .002). The most significant difference in PFS was observed in patients with GR KIR3DS1(+) in whom HLA-Bw4, the ligand for the corresponding inhibitory receptor KIR3DL1, was missing. Patients with KIR3DS1(+) KIR3DL1(+) HLA-Bw4(-) had a significantly shorter PFS than patients who were KIR3DS1(-), translating to a difference in median PFS of 12 months (12.2 vs 24 months; P = .002). Our data show that KIR-human leukocyte antigen immunogenetics represent a novel prognostic tool for patients with myeloma, shown here in the context of ASCT, and that KIR3DS1 positivity may identify patients at greater risk of progression.