Kena C. Miller

Rituximab in combination with CHOP or fludarabine in low-grade lymphoma

Non-Hodgkins lymphoma (NHL) is composed of a group of lymphoid malignancies that has been increasing in incidence at an annual rate of 4% to 7% over the last 20 years in both the United States and Europe. The reasons for this rise in incidence in NHL are not yet defined but most likely involve environmental exposures. Low-grade and follicular lymphomas account for approximately 40% of the incidences of NHL in the United States. While patients with intermediate- and high-grade lymphomas are potentially curable with combination chemotherapy, low-grade and follicular lymphomas are still considered to be essentially incurable with standard therapy. Although low-grade lymphomas characteristically respond well to treatment with chemotherapeutic agents, the disease typically follows a course of recurrent relapse and progressively shorter remissions, and ultimately death from lymphoma. Median survival for patients with low-grade lymphoma is 6.2 years from diagnosis and just 5 years from time of first relapse. Therefore, novel therapeutic strategies are urgently needed for these patients. One approach to the development of innovative strategies for treatment of NHL has been the generation of monoclonal antibodies to specific B-cell antigens expressed on NHL cells. Semin Oncol 29 (suppl 2):36-40. Copyright

Efficacy of lenalidomide in patients with chronic lymphocytic leukemia with high-risk cytogenetics.

Patients with chronic lymphocytic lymphoma (CLL) with high-risk cytogenetics [del(11q)(q22.3) or del(17p)(p13.1)] have limited therapeutic options and their prognosis remains poor. This analysis was conducted to determine the clinical activity of lenalidomide in patients with high-risk disease. Relapsed/refractory patients with CLL enrolled in a phase II clinical trial who had del(11q)(q22.3) or del(17p)(p13.1) were included in this analysis. Patients received single agent lenalidomide for 21 days of the 4 week treatment cycle. The overall response rate among patients with high-risk cytogenetics was 38%, with 19% of patients achieving a complete response. Median progression-free survival was 12.1 months, which is higher than demonstrated with other agents in comparable patient populations. In addition, the estimated 2-year survival probability was 58%, demonstrating that the responses achieved with lenalidomide are durable, even in patients with CLL with high-risk disease with poor risk cytogenetics.

Tumor flare reaction associated with lenalidomide treatment in patients with chronic lymphocytic leukemia predicts clinical response.

In patients with chronic lymphocytic leukemia (CLL), treatment with lenalidomide induces a unique, previously uncharacterized, immune response called tumor flare reaction (TFR). The clinical significance of this reaction remains unknown.

Plasma cell leukaemia and other aggressive plasma cell malignancies.

Extramedullary plasma cell cancers, such as plasma cell leukaemia (PCL) and multiple extramedullary plasmacytomas (MEP) are very aggressive malignancies. These can be primary (de‐novo) or secondary due to progressive prior multiple myeloma (MM). Recent reports suggest an increase in incidence of these disorders. Compared to MM, organ invasion is common in PCL, while soft tissue tumors involving the head, neck or paraspinal area are common sites for MEP. Markers of poor prognosis are frequently observed in these extramedullary forms of plasma cell cancers, and survival is significantly inferior compared to patients with MM. Conventional chemotherapeutic and radiotherapy approaches have been employed with variable results. Even high dose chemotherapy with autologous stem cell rescue has not been able to demonstrate consistent improvement in survival outcome. Although not specifically evaluated, novel anti‐plasma cell agents, such as the proteasome inhibitor bortezomib, and immunomodulatory drugs, such as lenalidomide, appear to be active against these aggressive cancers. Clinical and translational research directed at improved understanding of disease biology and development of novel therapeutics is urgently needed.

Long-term survival with allogeneic stem cell transplant and donor lymphocyte infusion following salvage therapy with anti-CD52 monoclonal antibody (Campath) in a patient with α/β hepatosplenic T-cell non-Hodgkin's lymphoma

Hepatosplenic T-cell non-Hodgkins lymphoma (HSTCL) is a rare, aggressive form of NHL, with a median survival of approximately 8 months. We were able to successfully induce complete remission in a patient with alpha/beta HSTCL who was refractory to multiple prior chemotherapy regimens, using the humanized anti-CD52 monoclonal antibody alemtuzumab (Campath). Once disease was controlled, the patient was able to undergo allogeneic stem cell transplantation (SCT), which resulted in complete remission. Furthermore, upon relapse, we were able to re-induce complete clinical and molecular remission with donor lymphocyte infusions. At Day 655 (post-SCT), the patient remains in complete remission. These data suggest a potential role for alemtuzumab and allogeneic SCT in the treatment of T-cell NHL.

Bortezomib in combination with pegylated liposomal doxorubicin and thalidomide is an effective steroid independent salvage regimen for patients with relapsed or refractory multiple myeloma: results of a phase II clinical trial

Novel agents have demonstrated enhanced efficacy when combined with other antimyeloma agents especially dexamethasone. The steroid doses employed in myeloma regimens are often poorly tolerated. Therefore, in a phase II clinical trial we investigated the efficacy of a steroid-free combination including bortezomib, pegylated liposomal doxorubicin and thalidomide (VDT regimen). Twenty-three patients with relapsed or refractory myeloma or other plasma cell cancers were treated with the VDT regimen. Patient had a median of five prior therapies and 65.2% were refractory to their last regimen. The overall response rates were 55.5% and 22%, respectively. The median progression free survival was 10.9 months (95% CI: 7.3–15.8) and the median overall survival was 15.7 months (95% CI: 9.1–not reached). Fatigue and sensory neuropathy were the most common side effects noted. We observe that VDT is an effective steroid-free regimen with ability to induce durable remission even in patients with refractory myeloma.

Prospective evaluation of low-dose warfarin for prevention of thalidomide associated venous thromboembolism

Venous thromboemobolism (VTE) is an important complication of thalidomide therapy especially when it is combined with steroids or chemotherapy. Currently there is no consensus on the most appropriate prophylactic approach. We prospectively investigated the use of low-dose warfarin sodium in prevention of thalidomide-associated VTE in patients receiving thalidomide-based combination therapies. Patients with multiple myeloma or chronic lymphocytic leukemia who were treated on thalidomide based-combination therapies were treated on low-dose warfarin (1 or 2 mg) continuously through the duration of their therapy. Among the 68 patients enrolled, four developed an episode of VTE, an overall incidence of 5.9% (odds = 0.063). Median duration of thalidomide therapy was 4 months. Low-does warfarin decreases the incidence of VTE compared to historical control and is an effective mechanism of prevention of VTE in thalidomide-based chemotherapy regimens.

Velcade, Doxil and Thalidomide (VDT) is an effective salvage regimen for patients with relapsed and refractory multiple myeloma

Multiple myeloma is an incurable disorder of malignant plasma cell. Standard therapy consists of high-dose melphalan followed by autologous stem cell transplant (SCT) [1]. Despite this aggressive approach all patients eventually relapse and die of the disease. Patients with relapsed and refractory multiple myeloma have limited treatment options. Thalidomide is an effective salvage therapy especially in combination with dexamethasone [2 – 4]. Recently, Richardson et al. reported on the clinical efficacy of bortezomib in patient with relapsed and refractory multiple myeloma [5]. Even though thalidomide and bortezomib has made a significant impact in the management of patients with myeloma all patients eventually become refractory to further therapy. Seminal work done by Anderson et al. has shown that bone marrow microenvironment plays an important role in the myeloma cell growth, dissemination as well as development of resistance to therapy [6 – 8]. Thus targeting the microenvironment concurrently with the tumor cell itself can potentially have a more pronounced antitumor effect and may overcome resistance to therapy. In an attempt to overcome drug resistance rationale new combinations using novel drugs with non overlapping toxicity and non cross resistant mechanism of action are being explored with encouraging results. Orlowski et al. [9] have recently shown synergistic activity of bortezomib with liposomal adriamycin (Doxil). Based of these observations and the established effects of thalidomide and bortezomib on tumor microenvironment we used a combination of bortezomib, thalidomide and liposomal doxorubicin (Doxil) as salvage regimen for highly refractory patients with multiple myeloma who have failed all standard therapies. Bortezomib and thalidomide were used to target the microenvironment while Doxil was used as a cytotoxic agent, targeting the malignant myeloma cell. We treated six patients with highly refractory multiple myeloma who failed standard therapies, with a combination of velcade, doxil and thalidomide (VDT). Velcade was given at a dose of 1.3 mg/m on days 1, 4, 15 and 18, doxil 20 mg/m on days 1 and 15 on a 30-day cycle. Low-dose thalidomide (100 – 200 mg) was given daily throughout the treatment cycles. While all patients had failed an anthracycline based therapy as well as thalidomide (either alone or in combination with steroids) four patients had also failed SCT and one patient had failed velcade. Two patients had progressive renal insufficiency from light chain disease at the time of initiating treatment. The demographic data of these patients are summarized in Table I. Objective response was noted in all six patients at the completion of the induction cycle. Patients were thereafter evaluated at the completion of each cycle prior to institution of the subsequent cycle. Median number of cycles given was four (range 2 – 6.5). While two patients achieved complete remission with negative immunofixation for monoclonal protein, one patient achieved a PR and three had stable disease (Table II). Median duration of response was 11.5 months (range 2 – 14+ ). The two patients with renal failure improved their serum creatinine to normal levels and were able to avoid impending hemodialysis. Using the paradigm to target the tumor cell as well as its microenvironment we were able to achieve clinically meaningful benefit in patients with highly refractory disease. Our clinical observations support

Acyclovir Prophylaxis against Varicella Zoster Virus Reactivation in Multiple Myeloma Patients Treated with Bortezomib-Based Therapies: A Retrospective Analysis of 100 Patients

BACKGROUND Previous studies have indicated that, in patients with multiple myeloma (MM), bortezomib is associated with an increased incidence of herpes zoster, resulting from reactivation of latent varicella zoster virus (VZV). OBJECTIVE Our objective was to determine whether increased risk of VZV reactivation could be abrogated by using prophylactic acyclovir. METHODS We retrospectively evaluated 100 consecutive MM patients treated with bortezomib-based therapies at the Roswell Park Cancer Institute for development of herpes zoster. Frontline and relapsed/refractory patients were included, and patients received bortezomib alone or in combination with agents such as doxorubicin, melphalan, or dexamethasone. All patients received >4 weeks of acyclovir prophylaxis (400 mg twice daily), which was initiated prior to starting treatment with bortezomib and discontinued 4 weeks following bortezomib. RESULTS Median patient age was 62 years, 57% were male, and most (56%) had Durie-Salmon stage IIIA MM. None of the 100 MM patients receiving acyclovir prophylaxis developed herpes zoster during treatment with bortezomib, irrespective of patients receiving a wide variety of concomitant antimyeloma therapies and regardless of response to bortezomib-based therapy. One additional patient, found to be noncompliant with acyclovir therapy, experienced VZV reactivation, having received 3 cycles of bortezomib (3 weeks each cycle) in combination with cyclophosphamide and dexamethasone. LIMITATIONS Limitations of the study include its small size and retrospective nature. CONCLUSIONS The increased risk of VZV reactivation observed in previous studies of bortezomib-based therapy was completely abrogated in this series of patients who received prophylaxis with acyclovir.

Development and characterization of a novel human Waldenström macroglobulinemia cell line: RPCI-WM1, Roswell Park Cancer Institute – Waldenström Macroglobulinemia 1

Abstract Understanding the biology of Waldenström macroglobulinemia is hindered by a lack of preclinical models. We report a novel cell line, RPCI-WM1, from a patient treated for WM. The cell line secretes human immunoglobulin M (h-IgM) with κ-light chain restriction identical to the primary tumor. The cell line has a modal chromosomal number of 46 and harbors chromosomal changes such as deletion of 6q21, monoallelic deletion of 9p21 (CDKN2A), 13q14 (RB1) and 18q21 (BCL-2), with a consistent amplification of 14q32 (immunoglobulin heavy chain; IgH) identical to its founding tumor sample. The clonal relationship is confirmed by identical CDR3 length and single nucleotide polymorphisms as well as a matching IgH sequence of the cell line and founding tumor. Both also harbor a heterozygous, non-synonymous mutation at amino acid 265 in the MYD88 gene (L265P). The cell line expresses most of the cell surface markers present on the parent cells. Overall, RPCI-WM1 represents a valuable model to study Waldenström macroglobulinemia.