Guido Bisping

Bortezomib in combination with intermediate-dose dexamethasone and continuous low-dose oral cyclophosphamide for relapsed multiple myeloma

A phase 2 trial was performed to study the combination of bortezomib (VELCADE®) with intermediate‐dose dexamethasone (DEX), and continuous low‐dose oral cyclophosphamide (CY) in patients with relapsed multiple myeloma (MM). Fifty‐four patients with advanced MM were enroled to receive eight 3‐week treatment cycles with bortezomib 1·3 mg/m2 on days 1, 4, 8, and 11, followed by three 5‐week cycles with bortezomib 1·3 mg/m2 on days 1, 8, 15, and 22. Within all cycles, DEX 20 mg/d was given orally on the day of bortezomib injection and the day thereafter. In addition, patients received CY continuous oral treatment at a dose of 50 mg/d p.o. once daily. Fifty patients completing at least one treatment cycle were evaluable for response. Complete, partial, and minor responses occurred in 16%, 66% and 8% of patients, respectively; overall response rate 90% (efficacy analysis). Median event‐free survival was 12 months, with a median overall survival of 22 months. Adverse events (AE) of grades 3 or 4 occurring in at least 10% of patients comprised leucopenia, infection, herpes zoster, thrombocytopenia, neuropathy and fatigue. Bortezomib combined with DEX and CY is a highly effective treatment for relapsed MM at an acceptable rate of grade 3/4 AE. Antiviral prophylaxis appears to be mandatory.

Hyperfractionated cyclophosphamide in combination with pulsed dexamethasone and thalidomide (HyperCDT) in primary refractory or relapsed multiple myeloma

Summary. Sixty patients with advanced multiple myeloma received 2–6 monthly treatment courses combining hyperfractionated cyclophosphamide (300 mg/m2 i.v. over 3 h q 12 h × 6, d 1–3) with pulsed dexamethasone (20 mg/m2/d p.o., d 1–4, 9–12, 17–20) and once daily thalidomide at individually escalating doses (100–400 mg/d) depending on tolerability (HyperCDT). Responding patients were maintained on daily thalidomide and monthly dexamethasone pulses. Complete, partial and minor response rates were 4%, 68% and 12% respectively; overall response rate was 84% (efficacy analysis). Median event‐free and overall survival was 11 and 19 months respectively. During at least one treatment cycle, 67% of patients experienced grade 4 neutropenia resulting in 17% grade 3 and 9% grade 4 infections. Side‐effects, presumably related to thalidomide, included neuropathy (40% grade 2, 16% grade 3), constipation (17%), oedema (5%), bradycardia (5%), skin reactions (3%), cerebrovascular events (5%) and deep vein thromboses (8%). Thromboses were not related to known thrombophilic risk factors. Four patients with prior myeloma therapy > 50 months developed myelodysplastic syndrome or secondary acute myeloid leukaemia 2–4 months after study entry. HyperCDT is a highly active and reasonably well‐tolerated salvage regimen in advanced or refractory multiple myeloma.

Bortezomib, Dexamethasone, and Fibroblast Growth Factor Receptor 3–Specific Tyrosine Kinase Inhibitor in t(4;14) Myeloma

Purpose: Novel drugs including targeted approaches have changed treatment paradigms for multiple myeloma (MM) and may also have therapeutic potential in the poor-prognosis t(4;14) subset; t(4;14) results in overexpressed and activated fibroblast growth factor receptor 3 (FGFR3). Blocking this receptor tyrosine kinase (RTK) induces apoptosis in t(4;14)+ MM cells and decreases adhesion to bone marrow stromal cells (BMSC). Using combinations of novel drugs, we investigated potential enhancement of single-agent activities within the tumor cells, targeting of the marrow micromilieu, or circumvention of drug resistance in t(4;14)+ MM. Experimental Design: We tested effects on apoptosis and related signaling pathways in the t(4;14)+ MM subset, applying drug combinations including a FGFR3 tyrosine kinase inhibitor (RTKI), the proteasome inhibitor bortezomib, and dexamethasone. Results: RTKI, bortezomib, and dexamethasone were active as single agents in t(4;14)+ MM. RTK inhibition triggered complementary proapoptotic pathways (e.g., decrease of Mcl-1, down-regulation of p44/42 mitogen-activated protein kinase, and activation of proapoptotic stress-activated protein/c-Jun NH2-terminal kinases). Synergistic or additive effects were found by combinations of RTKI with dexamethasone or bortezomib. In selected cases of t(4;14)+ MM, triple combinations were superior to dual combinations tested. Prevention from MM cell apoptosis by BMSC or exogenous interleukin-6 was circumvented by drug combinations. In t(4;14)+, N-ras–mutated NCI-H929 cells, resistance to RTKI was overcome by addition of dexamethasone. Notably, the combination of RTKI and dexamethasone showed additive proapoptotic effects in bortezomib-insensitive t(4;14)+ MM. Conclusions: Combining novel drugs in poor-prognosis t(4;14)+ MM should take into account at least bortezomib sensitivity and probably Ras mutational status.

Cancer Screening in Patients with Idiopathic Venous Thromboembolism--a Position Paper of the German Society of Hematology and Oncology Working Group on Hemostasis.

Cancer can trigger thromboembolism. There is a 4-10% chance of finding an asymptomatic occult cancer in patients with idiopathic venous thromboembolism (VTE). Current guidelines recommend limited cancer screening with history, physical examination, and screening examinations according to age after idiopathic VTE. Recent studies found that a more extensive screening program, including endoscopy and computed tomography, may increase the cancer detection rate. The Hemostasis Working Group of the German Society of Hematology and Oncology recommends a more extensive screening program after idiopathic VTE.

Diagnosis, prevention, and management of bleeding episodes in Philadelphia-negative myeloproliferative neoplasms: recommendations by the Hemostasis Working Party of the German Society of Hematology and Medical Oncology (DGHO) and the Society of Thrombosis and Hemostasis Research (GTH)

Philadelphia-negative myeloproliferative neoplasms (Ph-negative MPN) comprise a heterogeneous group of chronic hematologic malignancies. The quality of life, morbidity, and mortality of patients with MPN are primarily affected by disease-related symptoms, thromboembolic and hemorrhagic complications, and progression to myelofibrosis and acute leukemia. Major bleeding represents a common and important complication in MPN, and the incidence of such bleeding events will become even more relevant in the future due to the increasing disease prevalence and survival of MPN patients. This review discusses the causes, differential diagnoses, prevention, and management of bleeding episodes in patients with MPN, aiming at defining updated standards of care in these often challenging situations.

Combination of romiplostim and rituximab: effective therapy of severe immune thrombocytopenia

To the Editor: Immune thrombocytopenia (ITP) leads to accelerated platelet destruction accompanied by reduced platelet production. Here, we describe two patients with severe ITP that were successfully treated with a combination of romiplostim and rituximab. A 59-year-old woman was referred for relapsed ITP. Splenectomy was not possible because of a platelet count of 1000 ⁄lL and signs of bleeding. Further analysis revealed high-titer anti-platelet antibodies in the serum and increased numbers of megakaryocytes in the bone marrow. Initial treatment with prednisolone and intravenous immunoglobulins (IVIG), followed by dexamethasone and anti-rhesus-D immunoglobulin, did not lead to any significant increase in the platelet counts. As the disease was unresponsive to therapy(1), administration of romiplostim was initiated on day 1 (1 lg ⁄kg) with subsequent dose increases (1 lg ⁄kg per week) up to a dose of 6 lg ⁄kg on day 34 after the first dose of romiplostim without any change in platelet counts (Fig. 1). Platelet transfusions as well as administration of dexamethasone, factor XIII, and tranexamic acid were necessary for acute and life-threatening bleeding episodes. Rituximab (375 mg ⁄m) was given on day 40 and day 47 after the first dose of romiplostim, and the last dose of romiplostim (7 lg ⁄kg) was administered on day 41. Platelet counts increased from 3000 ⁄ lL and 6000 ⁄ lL on days 40 and 44 to 239 000 ⁄ lL on day 47. Both romiplostim and rituximab were stopped on day 47, and thromboprophylaxis was started. Platelet counts continued to rise to 1 053 000 ⁄ lL on day 53. Three weeks later, when platelets began to decrease again, the patient decided to undergo splenectomy as definite treatment for ITP. Afterward, platelet counts remained stable (between 500 000 and 600 000 ⁄lL). No further bleeding episodes occurred. Our second patient, a 25-year-old female with a history of two relapses of Hodgkin’s disease was admitted for newly onset petechiae (platelets 4000 ⁄ lL) 1 year after having completed her last chemotherapy and autologous transplant. Direct monoclonal antibody immobilization of platelet antigen (MAIPA) was positive, and bone marrow examination showed an increased megakaryocyte count. Bleeding was initially controlled by IVIG as well as steroids. In light of potential graft failure after multiple previous chemotherapies, an autologous stem cell boost (8.9 · 10 CD34 cells ⁄kg) was given. After more than 4 weeks without response (platelets 4000 ⁄ lL), administration of romiplostim was started (1 lg ⁄kg) (Fig. 1). Seven days later, the patient developed an acute headache. Magnetic resonance tomography of the brain revealed punctual cerebral hemorrhage, and platelet transfusions were administered. Rituximab (375 mg ⁄m weekly) was given on days 12, 19, 26, and 33 after romiplostim treatment initiation. On day 25, platelets increased to 41 000 ⁄ lL and continued to rise to normal levels, and romiplostim doses were not further escalated (4 lg ⁄kg). Interestingly, platelet counts decreased when romiplostim was tapered. ITP patients show a significant decrease in platelet production(2). Romiplostim, a novel thrombopoiesisstimulating protein, effectively binds and activates the human thrombopoietin receptor(3, 4). Clinical trials with romiplostim and eltrombopag(5, 6) have shown sustained elevations of platelet counts in patients with ITP either before or after splenectomy. Previously, romiplostim was combined with corticosteroids, azathioprin, danazol, or other drugs. However, to our knowledge, a combination with rituximab has not been described, although one patient receiving romiplostim 4 weeks after rituximab has been described(3). We reasoned that in cases of ITP unresponsive to both first-line therapy and romiplostim monotherapy, a combination of rituximab and romiplostim may inhibit platelet destruction and at the same time increase platelet production. Indeed, as seen in both cases, this combination can lead to a strong and even overwhelming increase in platelet counts. Frequent laboratory examinations and thromboprophylaxis are therefore necessary to prevent adverse reactions such as thrombotic events. Furthermore, our data reinforce existing recommendations of careful romiplostim dose increases to prevent uncontrolled increases in platelet counts. In the first case, the long latency of platelet increase after romiplostim initiation, the steep increase with rituximab, and the extent of the platelet response to up to 1 000 000 ⁄ lL which is uncommon for rituximab alone(7) strongly suggest that rituximab played a major role in the platelet response. This platelet response to rituximab may be explained by prestimulated thrombopoiesis as a doi:10.1111/j.1600-0609.2009.01406.x European Journal of Haematology 84 (362–364)