VTD-melphalan is well tolerated and results in very high rates of stringent CR and MRD-negative status in multiple myeloma.

The addition of cytotoxic drugs to high-dose melphalan as a preparative regimen for autologous stem cell transplantation in multiple myeloma has not resulted in superior activity. Although novel agents have significantly improved outcome in multiple myeloma, their role in preparative regimens remains largely unknown. We have evaluated the toxicity and efficacy of combining bortezomib, thalidomide, and dexamethasone with high-dose melphalan. An institutional review board-approved retrospective analysis was performed on 100 consecutive patients receiving 153 transplants; 53 had tandem transplants; 64 patients received early transplants; and 36 had salvage transplantation. Endpoints were treatment-related toxicity and mortality, and quality of response post-transplantation with assessment of stringent complete remission (sCR) and minimal residual disease (MRD) status. Median age was 61 years, and median follow-up was 16.2 months. At 6 months, sCR was attained in 56% of patients and CR in 20%. An MRD status, assessed by sensitive (10-4) multiparameter flow cytometry, was achieved in 85%. The 100-day mortality rate was 2.6% (4/153); 1.8% for early transplants and 4.5% for salvage transplants. Grade 3-5 non-hematologic toxicities were mainly related to metabolism/nutrition; gastrointestinal and infectious problems. Median time to absolute neutrophil count of >500/µL was 12 days for both early and salvage transplantations. No significant differences in quality of response were observed between early and salvage transplantation or between single and tandem autologous stem cell transplantation. Since both sCR and MRD are excellent early surrogate markers for progression-free and overall survival, this regimen will likely be superior to melphalan alone, but it needs to be formally assessed in a randomized study.

Potential pitfalls of serum free light chain analysis to assess treatment response for multiple myeloma.

Response to treatment in patients with a plasma cell disorder is typically measured by evaluating the bone marrow and myeloma markers, including monoclonal protein spike and immunofixation (IFE) in blood and urine, and serum free light chains (sFLCs). Stringent complete response criteria for Multiple Myeloma (MM) patients require a normal FLC ratio and absence of clonal cells in bone marrow by immunohistochemistry or immunofluorescence. We performed a retrospective chart review to further evaluate these criteria. A total of 142 patient charts were analysed. Of these, 17 patients were found to have an abnormal sFLC ratio, but no other evidence of disease, including normal flow cytometry and normal fluorescence in situ hybridization (FISH) analysis on highly selected plasma cells. In all patients, the abnormal sFLC ratio was caused by abnormalities in the serum kappa light chains. These results suggest that current definitions may need to be revised to take aberrancies related to abnormal immune recovery into account.

Current role of radiation therapy for multiple myeloma.

BACKGROUND: Radiation therapy (RT) is a treatment modality traditionally used in patients with multiple myeloma (MM), but little is known regarding the role and effectiveness of RT in the era of novel agents, i.e., immunomodulatory drugs and proteasome inhibitors. METHODS: We retrospectively reviewed data from 449 consecutive MM patients seen at our institute in 2010-2012 to assess indications for RT as well as its effectiveness. Pain response was scored similarly to RTOG 0631 and used the Numerical Rating Pain Scale. RESULTS: Among 442 evaluable patients, 149 (34%) patients and 262 sites received RT. The most common indication for RT was palliation of bone pain (n = 109, 42%), followed by prevention/treatment of pathological fractures (n = 73, 28%), spinal cord compression (n = 26, 10%), and involvement of vital organs/extramedullary disease (n = 25, 10%). Of the 55 patients evaluable for pain relief, complete and partial responses were obtained in 76.4 and 7.2%, respectively. Prior RT did not significantly decrease the median number of peripheral blood stem cells collected for autologous transplant, even when prior RT was given to both the spine and pelvis. Inadequacy of stem cell collection for autologous stem cell transplant (ASCT) was not significantly different and it occurred in 9 and 15% of patients receiving no RT and spine/pelvic RT, respectively. None of the three cases of therapy-induced acute myelogenous leukemia/MDS occurred in the RT group. CONCLUSION: Despite the introduction of novel effective agents in the treatment of MM, RT remains a major therapeutic component for the management in 34% of patients, and it effectively provides pain relief while not interfering with successful peripheral blood stem cell collection for ASCT.

Phase I/II study of clofarabine, etoposide, and mitoxantrone in patients with refractory or relapsed acute leukemia.

BACKGROUND: Clofarabine, a second-generation nucleoside analogue, was studied in combination with etoposide and mitoxantrone in acute leukemia. PATIENTS AND METHODS: In the phase I portion of this study clofarabine was given 20 or 25 mg/m(2) daily for 5 days (Days 2-6) with etoposide 100 mg/m(2) from day 1 to 5 and mitoxantrone 8 mg/m(2) from day 1 to 3. The dose-limiting toxicity was myelosuppression, and dose level 1, with clofarabine 20 mg/m(2) daily for 5 days was identified as the phase 2 dose. In total, 22 patients with relapsed or refractory acute myeloid leukemia (n = 18) and acute lymphocytic leukemia (n = 4) were treated. RESULTS: Five of 22 patients (23%) achieved complete response (CR), and 3 (13%) achieved CR with incomplete platelet recovery; an overall response rate of 36%. Median overall survival was 167 days (range, 22-1327 days). For 2 patients this regimen represented an effective bridge to allogeneic stem cell transplantation. CONCLUSION: Clofarabine in combination with etoposide and mitoxantrone is tolerable and shows significant activity in relapsed and refractory acute leukemia in adults.

Second autologous stem cell transplant: an effective therapy for relapsed multiple myeloma.

Therapeutic options for patients with multiple myeloma (MM) whose disease has relapsed after a prior autologous stem cell transplant (ASCT) include an expanding armamentarium of novel agents, often combined with traditional chemotherapy, or a second ASCT, with no clear standard of care. We retrospectively analyzed the outcomes of 75 patients who underwent salvage melphalan-based ASCT for relapsed MM at Memorial Sloan-Kettering Cancer Center between 1995 and 2012. Conditioning was performed with melphalan 200 mg/m(2) (n = 43), 180 mg/m(2) (n = 1), 140 mg/m(2) (n = 22), and 100 mg/m(2) (n = 9). The median age at second ASCT was 59 years (range, 36 to 75), and 58% (n = 35) were men. Of those with available data, 19% had high-risk cytogenetics (including t (4;14), p53 loss, or del 13q by karyotype) at the time of second ASCT. Median interval between first and salvage ASCT was 37.5 months (range, 6.9 to 111.4). Of 72 assessable patients, 57% had chemotherapy-sensitive disease before to salvage ASCT and 43% were chemoresistant. Four patients died within 100 days of ASCT. Response was assessed at 2 to 3 months post-ASCT, and of 71 assessable patients, 82% achieved at least a partial response, 15% had stable disease, and 3% progressed despite salvage ASCT. After salvage ASCT, 38 patients received maintenance therapy and 14 went on to allogeneic ASCT. The median progression-free survival (PFS) after second autograft was 10.1 months (95% confidence interval [CI], 7.6 to 13.4) and median overall survival (OS) 22.7 months (95% CI, 19.2 to 41.2). Patients with chemosensitive relapse had a trend toward better PFS (hazard ratio [HR], .60 [95% CI, .36 to 1.02]; P = .058) and significantly longer OS (HR, .49 [95% CI, .27 to .88]; P = .017) than patients with resistant relapse. Those with high-risk cytogenetics at the time of second ASCT had higher risk of death (HR, 2.98 [95% CI, 1.28 to 6.97]; P = .012) compared with patients with standard-risk cytogenetics. Salvage ASCT is an effective strategy for relapsed MM with chemosensitive disease and results in comparable PFS and OS to other salvage strategies.

Thalidomide-induced hemorrhagic rash in a patient with myelofibrosis and delta-granule storage pool disease.

Thalidomide is one of the immunomodulating agents used in current oncology practice. We present a case of hemorrhagic rash induced by thalidomide in a patient with delta granule storage pool disease. The patient was getting thalidomide for underlying myelofibrosis.

Gaps in pre-rituximab hepatitis B screening: an institutional experience.

The aim of the study was to evaluate the pretreatment workup of patients referred to our tertiary care center with low-grade lymphoma for compliance with National Comprehensive Cancer Network guidelines. This was a retrospective chart review. The study included all new patients with low-grade lymphoma who were diagnosed and treated at our center from January 1, 2005, to December 30, 2011. All the major facets of pretreatment workup were examined, including bone marrow biopsy, lactate dehydrogenase, hepatitis B screening, performance status of the patient, and diagnostic radiological studies. A total of 53 new patients were identified, of whom 36 (68%) had pretreatment workup and treatment at our center. The median age at diagnosis was 67. Fifty-four percent of the patients had bone marrow biopsy done. Radiological diagnostic studies were conducted in 97% of the patients. Hepatitis B screening was done in 19% of the total patients and 25% of the patients who received rituximab. Lactate dehydrogenase levels were checked in 72% of the patients. A significant deviation from the National Comprehensive Cancer Network guidelines for low-grade lymphoma pretreatment workup was observed for hepatitis B screening. Measures to ensure that patients have hepatitis B screening before rituximab were implemented. Studies such as these help to improve patient care.

Pulmonary collision tumor consisting of adenocarcinoma and typical carcinoid--a case report and review of literature.

Collision tumors are rare in nature. We report a case of a 70-year-old woman who was found to have a new mass in the right lung. Right upper and middle lobectomies with a mediastinal lymph node sampling were performed. Pathological examination of the mass revealed a collision tumor composed of micropapillary adenocarcinoma and typical carcinoid. The neoplastic cells were not intimately admixed with one another. To the best of our knowledge, this case is the first report in the English medical literature of a primary pulmonary collision tumor consisting of micropapillary adenocarcinoma and typical carcinoid.

Primary CNS lymphoplasmacytic lymphoma: a case report and review of literature.

Lymphoplasmacytic lymphoma is a chronic lymphoproliferative disorder characterized by a proliferation of plasma cells, small lymphocytes, plasmacytoid lymphocytes and the production of monoclonal IgM. Primary central nervous system lymphomas (PCNSL) are rare non-Hodgkin lymphomas (NHL) that can be found in the brain, leptomeninges, eyes or spinal cord, and are mostly intracerebral. PCNSLs constitute 3-4% of primary brain tumors, and in most cases are diffuse large B-cell lymphomas (DLBCL).(1) Low grade lymphomas as primary central nervous system (CNS) lymphoma are very rare. We present here a case report of a woman who presented with headache and was found to have primary intracranial lymphoplasmacytic lymphoma (LPL).

Current approaches to epigenetic therapy for the treatment of mantle cell lymphoma.

Epigenetics is the study of heritable changes in phenotype or gene expression caused by mechanisms other than changes in the underlying DNA sequence. Such changes can include DNA methylation or histone modifications which both serve to silence gene expression. This review describes a new development in pharmacology, epigenetic therapy, which attempts to correct these epigenetic changes for the treatment of mantle cell lymphoma (MCL) and other B cell malignancies for which no consensus on standard therapy exists. One class of drugs utilized are the histone deacetylase inhibitors, (HDACi) which result in the accumulation of acetylated histones. Hyperacetylation of histones and nonhistone proteins are postulated to mediate the anticancer effects of these drugs. Another class of epigenetic agents are hypomethylating agents, that can cause both DNA and histone hypomethylation. Epigenetic drugs may be useful in the treatment of cancer where hypermethylation of tumor suppressor genes is known to lead to silencing of these genes. The purine analog cladribine has been shown to have hypomethylating properties and has activity as a single agent or in combination with other therapies for mantle cell lymphoma. Epigenetic therapy with the DNA hypomethylating agent 5-aza-2-deoxycytidine can also cause restoration of cell surface expression of the CD20 protein and increase rituximab sensitivity in vitro. Combinations of epigenetic agents may act synergistically to further potentiate the efficacy of monoclonal antibodies like rituximab and ofatumumab and improve the treatment outcome in MCL.

Indolent Breast Lymphomas: A Case Series and Review of Literature.

Indolent breast lymphomas (IBL) are a rare form of extranodal lymphoma. There are very few reported cases of IBL presenting as a breast mass. We report two cases of IBL, a Marginal Zone Lymphoma (MZL) and a Small Lymphocytic Lymphoma (SLL), which were discovered on routine mammogram and later confirmed by biopsy and flow cytometery. Patient with MZL underwent chemotherapy and radiation therapy whereas patient with SLL was treated with chemotherapy alone.

Marginal zone lymphoma: old, new, targeted, and epigenetic therapies.

Marginal zone lymphoma (MZL) is an indolent B-cell lymphoma arising from marginal zone B-cells present in lymph nodes and extranodal tissues. MZL comprises 5-17% of all non-Hodgkin's lymphomas in adults. The World Health Organization categorizes MZL into three distinct types based on their site of impact: (1) splenic marginal zone lymphoma (SMZL); (2) nodal marginal zone lymphoma (NMZL); (3) extranodal mucosa-associated lymphoid tissue (MALT) lymphoma, which can be subdivided into gastric and nongastric. The subgroups of MZL share some common features but are different in their biology and behavior. Owing to the rarity of MZL there are few randomized trials available comparing various treatment options and therefore treatment is controversial, lacking standard guidelines. Treatment should be patient tailored and can range from a 'watchful waiting' approach for asymptomatic patients without cytopenias to surgery or localized radiation therapy. Rituximab in combination with chemotherapy has resulted in longer failure-free survival than chemotherapy alone in patients with SMZL. Helicobacter pylori positive gastric MALT shows a good response rate to triple antibiotic therapy. Newer therapies such as bendamustine, everolimus, lenalidomide, vorinostat and phosphoinositide 3-kinase inhibitors are in clinical trials for patients with relapsed or refractory MZL and have shown promising results. We are presently conducting clinical trials testing the efficacy of the epigenetic activity of cladribine as a hypomethylating agent in combination with the histone deacetylase inhibitor (HDACi) vorinostat and rituximab in patients with MZL. Further studies with the newer agents should be done both in newly diagnosed or relapsed/refractory MZL to streamline the care and to avoid the use of toxic chemotherapies as initial treatment.

Cladribine plus rituximab is an effective therapy for newly diagnosed mantle cell lymphoma.

Mantle cell lymphoma (MCL) is a non-Hodgkin lymphoma that is incurable with standard chemotherapy. There is no consensus on the best initial therapy, especially for elderly patients, who are not candidates for aggressive treatment approaches. Current National Comprehensive Cancer Network (NCCN) treatment guidelines include rituximab (R) plus cladribine for the initial treatment of MCL. However, few data are available to substantiate this recommendation. Therefore, to further define the role of R-cladribine for the initial treatment of MCL, we performed a retrospective chart review of 31 patients with MCL (median age, 67) treated with R-cladribine. The majority of responding patients also received R maintenance. The overall response rate was 87%, with 61% of patients achieving a complete remission (CR/CRu). The estimated median follow-up was 32.5 months, median PFS was 37.5 months, and median OS was 85.2 months. One of 19 (5.3%) subjects in CR/CRu relapsed (median follow-up of 23 months). CR/CRu was associated with improved survival (p < 0.0001), while a high mantle cell international prognostic index (MIPI) was associated with worse survival (p = 0.05). There was one toxic death (neutropenic pseudomonal sepsis) related to treatment. R-cladribine is an effective therapy for previously untreated MCL, and these results validate the use of R-cladribine for the initial treatment of MCL.