Nicolas Novitzky

Phase 3 Study of Recombinant Factor IX Fc Fusion Protein in Hemophilia B

BACKGROUND Prophylactic factor replacement in patients with hemophilia B improves outcomes but requires frequent injections. A recombinant factor IX Fc fusion protein (rFIXFc) with a prolonged half-life was developed to reduce the frequency of injections required. METHODS We conducted a phase 3, nonrandomized, open-label study of the safety, efficacy, and pharmacokinetics of rFIXFc for prophylaxis, treatment of bleeding, and perioperative hemostasis in 123 previously treated male patients. All participants were 12 years of age or older and had severe hemophilia B (endogenous factor IX level of ≤2 IU per deciliter, or ≤2% of normal levels). The study included four treatment groups: group 1 received weekly dose-adjusted prophylaxis (50 IU of rFIXFc per kilogram of body weight to start), group 2 received interval-adjusted prophylaxis (100 IU per kilogram every 10 days to start), group 3 received treatment as needed for bleeding episodes (20 to 100 IU per kilogram), and group 4 received treatment in the perioperative period. A subgroup of group 1 underwent comparative sequential pharmacokinetic assessments of recombinant factor IX and rFIXFc. The primary efficacy end point was the annualized bleeding rate, and safety end points included the development of inhibitors and adverse events. RESULTS As compared with recombinant factor IX, rFIXFc exhibited a prolonged terminal half-life (82.1 hours) (P<0.001). The median annualized bleeding rates in groups 1, 2, and 3 were 3.0, 1.4, and 17.7, respectively. In group 2, 53.8% of participants had dosing intervals of 14 days or more during the last 3 months of the study. In groups 1, 2 and 3, 90.4% of bleeding episodes resolved after one injection. Hemostasis was rated as excellent or good during all major surgeries. No inhibitors were detected in any participants receiving rFIXFc; in groups 1, 2, and 3, 73.9% of participants had at least one adverse event, and serious adverse events occurred in 10.9% of participants. These events were mostly consistent with those expected in the general population of patients with hemophilia. CONCLUSIONS Prophylactic rFIXFc, administered every 1 to 2 weeks, resulted in low annualized bleeding rates in patients with hemophilia B. (Funded by Biogen Idec; ClinicalTrials.gov number, NCT01027364.).

CD52 antibodies for prevention of graft-versus-host disease and graft rejection following transplantation of allogeneic peripheral blood stem cells

Graft-versus-host disease (GVHD) is a major cause of mortality and morbidity after allogeneic bone marrow transplantation, but can be avoided by removing T lymphocytes from the donor bone marrow. However, T cell depletion increases the risk of graft rejection. In this study, two strategies are used to overcome rejection: (1) use of high doses of stem cells obtained from peripheral blood (PBSC), (2) admixture with a CD52 monoclonal antibody in order to deplete both donor and residual recipient lymphocytes. Two antibodies are compared: CAMPATH-1G (rat IgG2b) and its humanized equivalent CAMPATH-1H (human IgG1). A total of 187 consecutive patients at six centers received PBSC transplants from HLA-matched siblings between 1997 and 1999. A wide spectrum of diseases, both malignant and non-malignant, was included. The recovery of CD34+ cells after antibody treatment was close to 100%. The risk of acute GVHD (grade 2 to 4) was 11% in the CAMPATH-1G group and 4% in the CAMPATH-1H group (P = NS). The risk of chronic GVHD (any grade) was 11% in the CAMPATH-1G group and 24% in the CAMPATH-1H group (P = 0.03) but the risk of extensive chronic GVHD was only 2%. The overall risk of graft failure/rejection was 2%, not significantly different between the two antibodies. Antibody treatment was equally effective at concentrations between 10 μg/ml and 120 μg/ml and it made no significant difference to the outcome whether the patients received post-transplant immunosuppression or not (87% did not). Transplant-related mortality in this heterogenous group of patients (including high-risk and advanced disease) was 22% at 12 months. It is proposed that treatment of peripheral blood stem cells with CAMPATH-1H is a simple and effective method for depleting T cells which may be applicable to both autologous and allogeneic transplants from related or unrelated donors. Special advantages of this approach are the simultaneous depletion of donor B cells (which reduces the risk of EBV-associated lymphoproliferative disease) and the concomitant infusion of CAMPATH-1H to deplete residual recipient T cells and thus prevent graft rejection. Bone Marrow Transplantation (2000) 26, 69–76.

One million haemopoietic stem-cell transplants: a retrospective observational study

BACKGROUND The transplantation of cells, tissues, and organs has been recognised by WHO as an important medical task for its member states; however, information about how to best organise transplantation is scarce. We aimed to document the activity worldwide from the beginning of transplantation and search for region adapted indications and associations between transplant rates and macroeconomics. METHODS Between Jan 1, 2006, and Dec 31, 2014, the Worldwide Network for Blood and Marrow Transplantation collected data for the evolution of haemopoietic stem-cell transplantation (HSCT) activity and volunteer donors in the 194 WHO member states. FINDINGS 953,651 HSCTs (553,350 [58%] autologous and 400,301 [42%] allogeneic) were reported by 1516 transplant centres from 75 countries. No transplants were done in countries with fewer than 300,000 inhabitants, a surface area less than 700 km(2), and a gross national income per person of US

Immune reconstitution after allogeneic bone marrow transplantation depleted of T cells.

1260 or lower. Use of HSCT increased from the first transplant in 1957 to almost 10,000 by 1985. We recorded a cumulative total of about 100,000 transplants by 1995, and an estimated 1 million by December, 2012. Unrelated donor registries contributed 22·3 million typed volunteer donors and 645,646 cord blood products by 2012. Numbers of allogeneic HSCTs increased in the past 35 years with no signs of saturation (R(2)=0·989). Transplant rates were higher in countries with more resources, more transplant teams, and an unrelated donor infrastructure. INTERPRETATION Our findings show achievements and high unmet needs and give guidance for decisions; to grant access for patients, to provide a donor infrastructure, and to limit overuse by defining risk and region adapted indications for HSCT as an efficient and cost-effective approach for life-threatening, potentially curable diseases. FUNDING Funding for this study was indirectly provided by support of the WBMT.

Hematopoietic stem cell transplantation activity worldwide in 2012 and a SWOT analysis of the Worldwide Network for Blood and Marrow Transplantation Group including the global survey

BACKGROUND Immune reconstitution following transplantation in individuals who had received T-cell-depleted marrow from HLA identical siblings was serially documented and correlated with the clinical recovery. METHODS Patients were preconditioned with radiation containing programs. GvHD prophylaxis was by T-cell depletion with CAMPATH 1G (ex vivo; median dose 20 mg). After transplantation lymphoid development was studied by flow cytometry and serum Ig concentrations were determined. Charts were reviewed to determine the effects of the immune reconstitution on the clinical performance. RESULTS The mean donor mononuclear cell number infused was 0.89x10(8)/kg. Within 6 months all the patients recovered their blood parameters and only one required therapy for GvHD. However, despite normal blood counts, 15 suffered life-threatening opportunistic infections, developing at a median of 24 weeks post grafting, but occurring even after 11 months. At 8 weeks from marrow infusion when leukocyte values had normalized in 15/20, compared to normal, immunophenotyping of blood cells from BMT revealed a significantly reduced mean lymphocyte count (1.06, SD 0.83x10(9)/l; P = 0.01), cells expressing CD3 (0.7x10(9)/l, SD 0.68; P = 0.05), CD4 (0.13x10(9)/l, SD 0.21; P = 0.0001) and CD19 (0.04x10(9)/l, SD 0.05; P = 0.001). Populations expressing CD8 and CD56 remained within normal range throughout the study. Normalization of cell numbers displaying CD2, CD3 and CD19 was delayed until 52, 52 and 24 weeks respectively, while CD4 counts persisted subnormal even at 72 weeks. Serum IgA levels were significantly decreased for the entire study period. CONCLUSIONS T-cell depletion with CAMPATH 1G while effectively preventing GvHD, also causes clinically significant and prolonged immunosuppression with apparently important clinical implications.

Thrombotic thrombocytopenic purpura in patients with retroviral infection is highly responsive to plasma infusion therapy

Data on 68 146 hematopoietic stem cell transplants (HSCTs) (53% autologous and 47% allogeneic) gathered by 1566 teams from 77 countries and reported through their regional transplant organizations were analyzed by main indication, donor type and stem cell source for the year 2012. With transplant rates ranging from 0.1 to 1001 per 10 million inhabitants, more HSCTs were registered from unrelated 16 433 donors than related 15 493 donors. Grafts were collected from peripheral blood (66%), bone marrow (24%; mainly non-malignant disorders) and cord blood (10%). Compared with 2006, an increase of 46% total (57% allogeneic and 38% autologous) was observed. Growth was due to an increase in reporting teams (18%) and median transplant activity/team (from 38 to 48 HSCTs/team). An increase of 167% was noted in mismatched/haploidentical family HSCT. A Strengths, Weaknesses, Opportunities, Threats (SWOT) analysis revealed the global perspective of WBMT to be its major strength and identified potential to be the key professional body for patients and authorities. The limited data collection remains its major weakness and threat. In conclusion, global HSCT grows over the years without plateauing (allogeneic>autologous) and at different rates in the four World Health Organization regions. Major increases were observed in allogeneic, haploidentical HSCT and, to a lesser extent, in cord blood transplantation.

Ex vivo depletion of T cells from bone marrow grafts with CAMPATH-1 in acute leukemia : Graft-versus-host disease and graft-versus-leukemia effect

We prospectively studied presentation biological differences and the response to therapy in patients with thrombotic thrombocytopenic purpura (TTP) associated with, or unrelated to human immunodeficiency virus (HIV) infection. TTP patients underwent standard evaluations and were treated with prednisone 1 mg/kg in addition to infusions of fresh frozen plasma (FFP; 30 ml/kg/d) until normalization of the platelet count. Unresponsive patients were referred for plasma exchange. Compared with HIV− TTP patients (n = 23), in HIV+ subjects (n = 21) microangiopathy was dominant among Black females, who had lower presentation Hb (median 5·8 g/dl; P = 0·03), platelet count (13 × 109/l; P = 0·05) and a CD4 count of 0·096 × 109/l. HIV+ individuals responded to FFP faster than HIV− patients and none of them required apheresis. Ten HIV− TTP patients required apheresis (P = 0·03) and four died. Responses in the HIV+ and HIV− groups occurred after treatment with a median of 33 and 55 units (one unit = 320 ml) of FFP (P = 0·004) respectively. Response to this protocol was seen in 84% (95% response in HIV+ patients). Regression analysis showed that survival was associated with younger age (P = 0·001), rapid platelet (P = 0·001) and Hb (P = 0·0009) recovery, and fewer FFP units to normal lactate dehydrogenase levels (P = 0·006). We conclude that in HIV+ individuals, microangiopathy is highly responsive to plasma infusions. This observation is important particularly when apheresis is not available.

Intravenous gammaglobulin has no advantages over oral corticosteroids as primary therapy for adults with immune thrombocytopenia: A prospective randomized clinical trial

BACKGROUND Preventing graft-versus-host disease (GVHD) by depletion of T lymphocytes from the stem cell graft for transplantation remains controversial, mainly because of the perceived increase in disease recurrence. METHODS We retrospectively analyzed the outcome of 50 consecutive individuals in remission of acute lymphoblastic leukemia (n=13; 8 in complete remission [CR]1) or acute myeloblastic leukemia (n=37; 33 in CR1), who had received marrow grafts from HLA-identical siblings. The conditioning regimen included six 2-Gy fractions of total body irradiation, succeeded by cyclophosphamide at 120 mg/kg (with mesna) followed by four fractions of 1.5 Gy to lymphoid areas. Bone marrow (n=38) or peripheral blood mobilized donor mononuclear cells (n=12) were exposed ex vivo to CAMPATH-1 (IgM and complement, or IgG; antiCD52) antibodies, without any further posttransplantation immunosuppression. RESULTS Median patient age was 31 (range 14-51) years; 12 patients were 40 or older. Thirty-two patients were male. One patient died of pulmonary hemorrhage on day 10; another died on day 29 of interstitial pneumonitis. Except for one early death, all patients engrafted. Ten (21%) of the remaining 48 who were at risk, developed GVHD. In none was it greater than grade II. Eight patients developed serious viral infections. Four died of cytomegalovirus pneumonia, adenovirus hepatitis, and human immunodeficiency. Overall, 11 patients (22%) relapsed (4 of 33 acute myeloblastic leukemia in CR1) at a median of 235 (range 46-528) days. Mean posttransplantation follow-up was 1062 (median 560; range 10-4177) days. Thirty-three patients (66%) remained disease free at a mean of 1,118 (median 1439; range 159-4,177) days. For all patients, the performance status was between 82% and 100% (median 100). CONCLUSION T-cell depletion with CAMPATH-1 effectively prevents GVHD, particularly the severe acute forms, without leading to excessive risk of relapse in acute leukemia.

Increased apoptosis of bone marrow cells and preserved proliferative capacity of selected progenitors predict for clinical response to anti-inflammatory therapy in myelodysplastic syndromes

Symptomatic immune thrombocytopenia in adults is potentially lethal, and, when conventionally treated with oral corticosteroid agents, approximately two thirds of patients will have some response in platelet count, but this is seldom durable. Since cytotoxic drugs are of limited benefit at this stage, splenectomy becomes necessary in 70% of patients. Intravenous gammaglobulin has been advocated as an alternative to prednisone as the primary form of treatment. A prospective, randomized comparison was carried out between oral prednisone (1 mg/kg/day; group 1; n = 17), high-dose intravenous gammaglobulin (400 mg/kg on days 1 through 5; group 2; n = 13), or a combination of both agents given on the same schedule (group 3; n = 13). The groups were well matched clinically and hematologically. No mortality occurred after initiating therapy, but one patient experienced a cerebrovascular accident. Response, defined as a platelet count greater than 50 x 10(9)/L, was achieved in 82%, 54%, and 92% of patients in groups 1, 2, and 3, respectively, but was only significant between groups 2 and 3 (P = 0.0365). The median times to peak platelet counts were 8.5 days (range 7 to 21 days), 7 (range 5 to 10 days), and 7 (range 3 to 23 days), respectively. Although there was a trend in favor of the steroid-administered groups, relapse was not significantly different, which occurred at a median of 184, 32, and 76 days, respectively, nor was the average time to splenectomy different at 339, 59, and 98 days, respectively. At a minimum of 2 years of follow-up, 5 of 17 in group 1, 2 of 13 in group 2, and 1 of 13 in group 3 had achieved platelet counts of greater than 100 x 10(9)/L and, therefore, did not require splenectomy. In contrast, where this indication was present for failure to respond, 8 of 12 (67%) in group 1, 4 of 8 (50%) in group 2, and 9 of 12 (75%) in group 3 remain in complete remission. Significantly more patients in group 2 than group 3 experienced a relapse (P = 0.0365). It is concluded that in previously untreated adults with symptomatic immune thrombocytopenia, gammaglobulin offers no advantage over conventional corticosteroid administration as the primary form of therapy. Additionally, more intense immunosuppression, resulting from the use of both agents combined, is no better than single agent corticosteroid agents and appears to be an unnecessary and unwarranted expense.

Myeloablative conditioning is well tolerated by older patients receiving T-cell-depleted grafts

To determine the relation of apoptosis and clonal proliferation in the bone marrow (BM) to the effectiveness of a therapeutic protocol described to downmodulate monokine activity in patients with myelodysplastic syndromes (MDS). Prior to protocol therapy, BM stroma was cultivated and selected CD34(+) cells were studied in stroma and cytokine-dependent clonogenic assays. The TUNEL assay was used to establish the degree of apoptosis occurring in the marrow and CD34(+) population. The effectiveness of oral ciproloxacin 500 mg b. i.d., pentoxifylline 800 mg t.i.d., and dexamathasone 4 mg t.i.d. (CPD) antiinflammatory therapy was correlated with the intensity of cell apoptosis and proliferation of BM progenitor cells. Seventeen patients were studied. Twelve patients (10 transfusion dependent) received therapy for a median of 99 days (range 49-284). Toxicity caused four patients to discontinue the drug combination. Six patients fulfilled response criteria. Four patients became transfusion independent, and 50% reduction in the need for blood transfusions was noted in one patient. Blood parameters of one untransfused patient increased by >30%. Blood count remained unsupported in three patients, even at a median of 12 months after trial discontinuation. Apoptosis of marrow cells and selected CD34(+) progenitors was detected in a median of 49.5% (range 3. 6%-90%) and 10.6% (range 3.6%-100%; p < 0.01), respectively. In patients who responded to therapy, the median apoptosis rate in the bone marrow population was 71%, in contrast to the nonresponders rate of 13% (p = 0.002). Overall clonogenic growth of selected precursors corresponded significantly with response to CPD protocol (p = 0.004). In some patients with MDS, ineffective hematopoiesis is related to high apoptotic index despite proliferation of the CD34(+) precursors. These patients seem to benefit from CPD cytokine modulatory therapeutic strategy.