Clinical Lymphoma Myeloma and Leukemia

Ten-Year Relative Survival and Causes of Death in Elderly Patients Treated With R-CHOP or CHOP in the GELA LNH-985 Trial

2012-02-02

Advances in lymphoma therapy have resulted in improved cure rates and an increasing number of long-term survivors. The addition of rituximab (R) to the standard treatment regimen composed of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) has greatly improved outcomes for elderly patients with diffuse large B-cell lymphoma (DLBCL). The R-CHOP regimen confers 2 major benefits: (1) a decrease in the number of patients with disease progression during treatment (ie, refractory patients) and (2) a decrease in the number of relapsing patients. The 10-year overall survival (OS) estimates of nearly 50% reported in recent studies are a strong indication that cure is a realistic objective in present trials of DLBCL therapy in elderly patients.

TRAF6 Activation in Multiple Myeloma: A Potential Therapeutic Target

2012-03-23

Abstract: Multiple myeloma (MM) is an incurable B-lymphocyte malignancy. New therapeutic options have become available during the past several years; however nearly all patients acquire resistance to currently available therapeutic agents. Mechanisms contributing to the pathogenesis and chemoresistance of MM include genetic abnormalities, chromosomal translocations, gene mutations, the interaction between MM cells and the bone marrow microenvironment, and defects in the apoptotic signaling pathways. Survival signaling pathways associated with the pathogenesis of MM and bone marrow stromal cells play crucial roles in promoting growth, survival, adhesion, immortalization, angiogenesis, and drug resistance. The receptor activator of nuclear factor-kappa B/receptor activator of nuclear factor-kappa B ligand/tumor necrosis factor receptor-associated factor (RANK/RANKL-TRAF6) signal pathway mediates osteolytic bone lesions through the activation of the NF-κB and Janus kinase/signal transducer and activator of transcription (JNK) pathways in osteoclast precursor cells and thus contributes to the main clinical manifestations of bone disease. TRAF6 has also been identified as a ligase for Akt ubiquitination and membrane recruitment and its phosphorylation on growth factor stimulation. The inhibition of TRAF6 by silencing RNA or by decoy peptides decreases MM tumor cell proliferation and increases apoptosis as well as bone resorption. Some proteasome inhibitors and benzoxadiazole derivatives showed inhibitory effects on the activity and function of TRAF6. Overall, we propose that TRAF6 may be considered as a potential therapeutic target for the treatment of MM.

Spectrum of Neurologic Complications in Chronic Lymphocytic Leukemia

Rodrigo Lopes da Silva — 2011-12-23

Abstract: Neurologic disease is believed to be an unusual complication during the course of chronic lymphocytic leukemia. Nevertheless, it has already been proven in autopsy series that the incidence of occult nervous system infiltration is much higher than was previously expected. The advent of more potent drugs to treat this lymphoproliferative disorder has brought a new hope for a possible cure in the future. However, an appropriate systemic treatment for central nervous system infiltration of this disease is still lacking. Also, due to the potent immunosuppressive properties of the agents used in the up-front treatment, for example, the purine nucleoside analogues, we have witnessed an increase in the incidence of opportunistic infections, with progressive multifocal leukoencephalopathy being one of the most serious. The goal of this review is to summarize the spectrum of neurologic derangements linked to chronic lymphocytic leukemia and to raise clinicians' awareness to recognize the possibility of such associations.

Pilot Study of Denileukin Diftitox Alternate Dosing Regimen in Patients With Cutaneous Peripheral T-Cell Lymphomas

Rakhshandra Talpur, Madeleine Duvic — 2012-04-23

Micro-Abstract: Better treatment and survival outcomes are needed for the rare primary cutaneous peripheral T-cell lymphomas. Five (62.5%) of 8 patients with peripheral T-cell lymphomas enrolled in a pilot study of denileukin diftitox at 18 μg/kg per day for 5 days followed by once weekly for 24 weeks responded, including 2 complete responses, one of which is ongoing at 8 years.Abstract: Purpose: To evaluate the safety and efficacy of an alternate dosing regimen in rare primary cutaneous peripheral T-cell lymphoma variants. Methods: This is a prospective, single center, pilot study of denileukin diftitox (Dd) in patients with persistent or recurrent cutaneous peripheral T-cell lymphomas and mycosis fungoides (MF) variants, excluding Sézary syndrome (SS). Dd was administered at 18 μg/kg per day for 5 days and once weekly for 24 weeks, with response by modified skin weighed assessment tool. Results: Eight patients, with a median age of 76 years (range, 44-88 years), were treated between December 2003 and July 2008. Five (62.5%) of 8 patients responded, including 3 patients with CD30+ anaplastic large-cell lymphoma (ALCL) with 2 complete responses, one ongoing at 8 years. One patient with CD8+ and 1 patient with natural killer T cell lymphoma (NK-T) had partial responses. Progressive disease occurred in 1 patient positive for human T-cell lymphotropic virus and 1 patient with ALCL. Vascular leak syndrome (VLS) occurred in 6 (75%) of 8 patients during or just after cycle 1. Three were grade 3, and 2 of these resulted in study withdrawal. Other adverse effects included nausea or vomiting (n = 3), fatigue (n = 1), back pain (n = 1), transaminase elevations (n = 3), and elevated creatinine (n = 1). Conclusions: Dd with an alternate dosing schedule was active in this small study of primary cutaneous T-cell lymphomas.

Phase II Trial of Syncopated Thalidomide, Lenalidomide, and Weekly Dexamethasone in Patients With Newly Diagnosed Multiple Myeloma

2012-03-01

Micro-Abstract: Thalidomide and lenalidomide, in combination with dexamethasone, provide response rates ranging from 63%-79% after 4 cycles of therapy. Because of toxicities such as neuropathy and myelosuppression for thalidomide and lenalidomide, respectively, dose escalation has not been pursued. We evaluated a syncopated regimen of alternating weeks of thalidomide and lenalidomide to determine if a modified schedule allows for fewer dose reductions and, subsequently, superior efficacy. Although well tolerated, this phase II trial did not show superior efficacy compared with conventional dosing and scheduling of these agents. Abstract: Introduction: Over the past decade, the novel agents thalidomide, lenalidomide, and bortezomib have emerged as effective treatment in patients with multiple myeloma (MM). Initially used in the relapse setting, these agents have been incorporated into frontline treatment algorithms. They have been combined in doublets with corticosteroids, in triplets with alkylators, or with each other. Because thalidomide and lenalidomide have different clinical activity and toxicity profiles, we designed a trial to evaluate a syncopated schedule of thalidomide and lenalidomide with weekly dexamethasone in patients with newly diagnosed MM to determine response and toxicity. Patients and Methods: Twenty-two patients with newly diagnosed MM were treated with syncopated thalidomide (200 mg on days 1-7 and 15-21), lenalidomide (25 mg on days 8-14 and 22-28 for the first cycle and 50 mg on the same schedule for subsequent cycles) with weekly dexamethasone (40 mg). Each cycle lasted 28 days. MM parameters were assessed at the end of each cycle. It was intended that the patients proceed to stem cell mobilization and autologous transplantation after 4 cycles of therapy. Results: The median number of cycles administered was 3.5. The overall response was 68%. The regimen was well tolerated by the majority of the patients; only patient discontinued treatment because of toxicity. Conclusion: We conclude that a syncopated schedule of thalidomide and lenalidomide with weekly dexamethasone was tolerated well, with no unexpected toxicities. However the response rate, even using lenalidomide at 50 mg, was not superior to standard dosing of thalidomide or lenalidomide plus dexamethasone.

Successful Treatment of Patients With Multiple Myeloma and Impaired Renal Function With Lenalidomide: Results of 4 German Centers

2012-02-20

Micro-Abstract: Retrospective multicenter analysis of 26 patients with multiple myeloma to assess the efficacy and toxicity of relapse treatment with lenalidomide/dexamethasone in renal-function impairment. Analysis showed myeloma overall response rate of 84%, with 42% of patients with improvement of renal function. Lenalidomide/dexamethasone is highly effective, with acceptable toxicity in the renally impaired patient group. Abstract: Purpose: Renal impairment is one of the main complications of multiple myeloma associated with unfavorable prognosis. Lenalidomide in combination with dexamethasone is an effective treatment of relapsed and/or refractory multiple myeloma and may be used in patients with myeloma and with renal insufficiency with appropriate dose adaption according to creatinine clearance (CLCr). However, there are limited data on the use of this regimen in patients with myeloma and with impaired renal function. Patients and Methods: We report on 26 patients, in 4 German centers, with impaired renal function and relapsed and/or refractory multiple myeloma who were treated with lenalidomide/dexamethasone–based regimens; we retrospectively analyzed their data. Results: All 26 patients had a CLCr < 60 mL/min. Six patients were permanently or temporarily dialysis dependent. Overall response rate (ie, at least a partial response) was 84%. The rate of renal response (at least minor renal response) was 42%, with 6 patients achieving a complete renal response. A median time of 28 days was documented until first response. Six patients had grade 3/4 thromboembolic events; all but one of these patients received prophylaxis with acetylsalicylic acid. Conclusion: Lenalidomide-based treatment is highly effective and is an attractive treatment option in patients with multiple myeloma with impaired renal function. In this analysis, renal function was improved in a substantial proportion of patients.

Phase I-II Study of Bendamustine in Patients With Acute Leukemia and High Risk Myelodysplastic Syndrome

2012-06-01

Micro-Abstract: A phase I-II study of bendamustine fractionated twice daily schedule for 4 days identified 75 mg/m2 intravenously (IV) twice daily for 4 days as a phase II study schedule. Abstract: Background: Alkylating agents have shown activity in leukemia. Bendamustine, an active alkylating agent in lymphoma and chronic lymphocytic leukemia, was given in a fractionated twice daily schedule for 4 days to patients with acute leukemia and myelodysplastic syndrome (MDS) to define the dose-limiting toxicities (DLT) and maximum tolerated dose (MTD). Patients and Methods: Adults with refractory acute leukemia or high-risk MDS were treated with bendamustine at a starting dose of 50 mg/m2 IV over 1-2 hours twice daily for 4 days. Dose escalations were by 25 mg/m2 in the 1st 3 levels. The study used the 3 + 3 design. Results: A total of 25 patients were treated. Their median age was 57 years; the median salvage number was 3. Grade 2 creatinine elevations were observed in 1 of 6 patients at the 50 mg/m2 dose, in 2 of 13 patients at the 75 mg/m2 dose, and in 3 of 6 patients at the 100 mg/m2 dose. This was considered significant, even though DLT was not reached. One patient achieved marrow complete remission. Significant reductions of marrow blasts (50% or more) were observed in 6 of 25 patients (24%). Conclusion: Bendamustine fractionated dose level of 100 mg/m2 IV twice daily for 4 days (800 mg/m2 per course) was associated with Grade 2 renal toxicity. The proposed phase II schedule is 75 mg/m2 IV twice daily for 4 days. Future studies should evaluate this schedule in less heavily treated patients.

IGHV3-21 Gene Frequency in a Swedish Cohort of Patients With Newly Diagnosed Chronic Lymphocytic Leukemia

2012-04-05

Micro-Abstract: The IGHV3-21 gene has been shown to be overrepresented in Scandinavian patients with chronic lymphocytic leukemia (CLL). By investigating a population-based cohort of 337 Swedish patients with CLL, a lower (6.5%) IGHV3-21 frequency was determined relative to our previous hospital-based studies (10.1%-12.7%), yet this frequency remained higher compared to other Western CLL cohorts (2.6%-4.1%). Furthermore, we confirmed the poor outcome for patients with IGHV3-21 to be independent of mutational and stereotypy status. Abstract: Background: Scandinavian patients with CLL have shown an overrepresentation of the poor-prognostic IGHV3-21 gene. Furthermore, approximately 50% of patients with IGHV3-21 carry stereotyped B-cell receptors, which implicate antigen selection in leukemogenesis. These patients have also been reported to have shorter time to progression than patients with nonstereotyped IGHV3-21. Materials and Methods: To investigate the IGHV3-21 frequency and the clinical impact of IGHV3-21 stereotypy, 337 newly diagnosed Swedish CLL patients from a population-based cohort were analyzed. Results: Interestingly, the IGHV3-21 frequency was indeed lower (6.5%) in this indolent patient cohort than in our previous hospital-based cohort studies (10.1%-12.7%). Hence, a selection bias of more-aggressive cases rendered a higher proportion of IGHV3-21 cases in our original studies. Nevertheless, the Swedish IGHV3-21 frequency still remained higher when compared with other larger European or American studies (2.6%-4.1%). Finally, we confirmed the poor outcome for IGHV3-21 patients to be independent of mutational status and found stereotypy to have no impact on survival or time to treatment. Conclusion: The Swedish geographic bias in IGHV3-21 gene frequency was validated albeit at a lower frequency than previously reported. Moreover, no prognostic value could be attributed to IGHV3-21 stereotype status.

Epigenetic Therapy With Hydralazine and Magnesium Valproate Reverses Imatinib Resistance in Patients With Chronic Myeloid Leukemia

2012-03-15

Micro-Abstract: The epigenetic drugs hydralazine and valproate were administered in a compassionate manner to 8 patients with chronic myeloid leukemia (CML) refractory to imatinib. Two patients had a complete hematologic response (25%), 1 major cytogenetic response, 1 complete cytogenetic response (25% any cytogenetic response), and 3 (37.5%) stable disease. No grade 3 or 4 toxicity was observed. These results show the ability of epigenetic therapy to revert imatinib resistance. Abstract: Background: Epigenetic alterations participate in the development of acquired resistance to imatinib, hence, the DNA methylation, and histone deacetylase inhibitors hydralazine and valproate, respectively, has the potential to overcome it. Patient and Methods: A series of 8 patients with chronic myeloid leukemia (CML) refractory to imatinib mesylate with no access to second-generation tyrosine kinase inhibitors were treated with hydralazine and valproate in a compassionate manner. Clinical efficacy and safety of these drugs added to imatinib mesylate were evaluated. Results: Two patients were in the blast phase, 5 were in the accelerated phase, and 1 was in the chronic phase. All the patients continued with the same dose of imatinib that they had been receiving at the time of development of resistance, with a median dose of 600 mg daily (range, 400-800 mg). The median time from diagnosis of CML to the start of hydralazine and valproate was 53.6 months (range, 19-84 months). Two (25%) patients had a complete hematologic response, one (12.5%) had an major cytogenetic response, and one (12.5%) had a complete cytogenetic response. Three (37.5%) patients had stable disease, and only one (12.5%) patient failed to respond. At a median follow-up time of 18 months (range, 3-18 months), the median survival had not been reached, and the projected overall survival was 63%. All the patients had mild neurologic toxicity, including distal tremor and somnolence. No grade 3 or 4 toxicity was observed. Conclusions: Our results suggest that the epigenetic drugs hydralazine and valproate revert the resistance to imatinib in patients with CML.

Non-Hodgkin Lymphoma in a Child With Neuroblastoma Preceding Autologous Stem Cell Transplant

Julie Blatt, Michael LaQuaglia, John P. Hunt, David E. Morris, Kimberly A. Kasow — 2012-06-01

Is the Angioimmunoblastic T-Cell Lymphoma Beneficial to Avoid CD4+ Lymphopenia and Other AIDS Manifestations in Patients Infected With Human Immunodeficiency Virus?

Julio A. Diaz-Perez, Gabriel A. Hurtado-Gomez, Juan S. Barajas-Gamboa — 2012-03-05

Syndrome of Inappropriate Antidiuretic Hormone Secretion due to Marginal Zone Lymphoma: Responding to Rituximab

Bruno Bockorny, Constantin A. Dasanu — 2012-06-01

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