Intensive Treatment Strategies Research Articles

Is Type of Monosomy (Total or Partial) Crucial for Prognostic Value of Monosomal Karyotype in AML Patients? – Preliminary Results of Retrospective Polish Adult Leukemia Group (PALG) Study,

Abstract 3537 Objectives:Cytogenetics is one of the most important prognostic factors in acute myeloid leukemia (AML). Breems et al., based on banding techniques (BT), have identified a monosomal karyotype (MK) to be associated with particularly poor survival. MK is defined by the presence of an autosomal monosomy in conjunction with at least one other autosomal monosomy or structural abnormality. However, classical BT may be not sufficient to confirm the “real” loss of a particular chromosome, especially in patients with complex karyotype (≥ 3 or ≥ 5 separate abnormalities) where parts of „missing” chromosomes could be involved in structural aberrations such as: additions, derivative chromosomes, rings, marker chromosomes and dicentrics. Molecular cytogenetic techniques, such as FISH, could be useful to verify if observed monosomy was “total” (loss of a complete chromosome) or “partial” (loss of only a part of chromosome including centromere).The aim of our study was to assess if the type of monosomy (total or partial), defined using FISH influences the prognosis of AML patients with MK.Materials and methods: Fifty newly diagnosed AML patients with MK, treated between January 2005 and January 2011 with PALG AML1/2004 and AML2/2004 protocols were included into the study. Cytogenetic analysis was performed on metaphases from bone marrow aspirates taken at diagnosis using standard BT. Karyotypes were centrally reviewed by two independent cytogeneticists and reported in accordance with the ISCN. In 41 cases FISH was performed with painting probes and in justified cases additionally with satellite probes and locus-specific probes to assess the type of monosomy. In 9 patients no confirmation by FISH was needed. Results:In 8/50 (16%) patients FISH verification proved the complex, but not monosomal (total or partial) karyotype. These patients were excluded from further study. The median age of 42 evaluable patients was 58 years (range 20–71 years). There were 26 males and 16 females. Twenty three (55%) patients received intensive induction chemotherapy according to PALG protocols (Holowiecki et al. Leukemia 2004), 8 patients - low dose cytarabine and 11 patients with high frailty index received treatment with hydroxyurea (n=9), and best supportive care (n=2).In 38/42 (90.5%) analyzed cases with MK abnormalities were complex. In all but one ≥5 separate aberrations were present. In 27/42 (64.3%) cases a total monosomy was confirmed by FISH (group A) and in 15/42 (35.7%) cases FISH revealed a monosomy to be the partial one (group B). Both groups A and B were comparable in terms of age, sex, immunophenotype and factors associated with tumor mass (leukemic bone marrow infiltration, WBC and peripheral blood blast count, as well as LDH activity). There was also no difference in the proportion of intensive and non-intensive treatment strategies between both groups. Six (26,1%) of intensively treated patients achieved complete remission (CR). The CR rate in patients with partial monosomy (40%) was higher than in total monosomy group (15,4%), however the difference was not significant (p=0.19; Fisher’s exact test). The median overall survival (OS) for all evaluable patients was 66 days (range 1–659 days) and the probability of OS at 1 yr was 14% (95% CI 4–23%). Total monosomy was the only factor associated with decreased probability of OS both in univariate (p=0.036) (Fig. 1) and multivariate (p=0.037) analyses in AML patients with MK. [Display omitted] Additionally, in patients with total monosomy the frequency of distinct monosomies was analyzed. The most frequent monosomies were monosomy 7 (n=13; 48%) and monosomy 18 (n=10; 37%). Other total monosomies included: monosomy 17 (n=3; 11%), monosomy 16 (n=2; 7%) and others (n=4). We did not observe any total monosomy 5. Conclusions:Our results indicate for the first time that partial monosomy is associated with significantly better OS than total monosomy in high risk AML with MK and provide further evidence for the heterogeneity of this defined cytogenetic group. These data also clearly demonstrate an important role of FISH method for precise evaluation of complex karyotype, which results in correct classification within MK group, as well as in adequate description of monosomy type. Disclosures:Wierzbowska:Genzyme: Membership on an entity's Board of Directors or advisory committees. Dmoszynska:Roche: Honoraria; Mundipharma:.

Leukocytosis and Circulating Blasts in Older Adults With Newly Diagnosed Acute Myeloid Leukemia: Are They Valuable Factors for Therapeutic Decision-Making?

The treatment of older adults with acute myeloid leukemia (AML) is associated with unsatisfactory rates of response and overall survival. Identification of valuable factors that can facilitate therapeutic decision-making between intensive chemotherapy and investigational treatment strategies is warranted. Analysis of proliferative (white blood cell [WBC] count) and invasive (percentage of blast cells in peripheral blood) characteristics of leukemic blasts at diagnosis is presented in a population of 432 promyelocytic leukemia AML patients who are older than than 60 years and have been selected for entering onto five successive clinical trials combining an anthracycline and cytarabine. Five groups of patients were defined according to these two relevant parameters used in clinical practice. Response rates were lower for the hyperproliferative groups (47% and 46%, respectively) and the nonproliferative groups displaying circulating blasts (56% and 59%, respectively) compared with those for the nonproliferative and noninvasive group (77%) (P = .0003). Median overall survivals were shorter for the hyperproliferative groups (5.7 and 5.8 months, respectively) compared with those observed for the nonproliferative groups (8.9 and12.6 months, respectively). This combination of basic characteristics helps estimate the outcome of elderly AML patients who are usually selected for intensive chemotherapy. Although these factors remain valuable for identifying leukemia behavior, our study demonstrated that results of intensive chemotherapy in elderly patients remained poor, whatever the prognostic group. Comparison with recent data from the literature requires investigators to study results differently and to consider investigational therapy as being the most appropriate treatment even for this highly selected population.

Ideal Blood Glucose Control for Type 2 Diabetes Management: A New Clinical Equipoise

Diabetes mellitus is a common chronic condition and an old friend to family physicians practising in the community. The long-standing practice had aimed to lower glucose levels in type 2 diabetes to prevent long-term complications. The recent evidence from some publications since June 2008 had suggested the possible harm to our patients when we adopt intensive treatment strategies with tight treatment control targets (below HbA1c of 6%) and many meta-analyses have been published. This review highlights the evidence from recent studies that shook the previous dogma and the new clinical equipoise.

Optimal care for early RA patients: the challenge of translating scientific data into clinical practice

Although the evidence is clear and most rheumatologists agree that RA should be treated early and intensively, it obviously remains a challenge to put this paradigm into practice. Patient- as well as physician-related factors determine the delay before the disease is recognized and treated appropriately. There is still a need for education in this context. Optimal treatment allocation depends on the determination of prognostic factors, but should also take into account the patient's perspective to be effective. Patients' perceptions about the disease and its medical management need to be adjusted as soon as possible. Initiation of intensive or complex treatment regimens is most feasible in a clinical setting, where rheumatologists work together with other health-care professionals, such as nurse specialists. Until now there does not seem to have been a difference in terms of efficacy between intensive RA treatment strategies based on a combination of classical DMARDs with glucocorticoids or with TNF-blocking agents, but given the costs biologicals cannot be considered first-line therapy. More scientific work is needed to identify individuals that could benefit from biologicals early in the disease. Given the long-term benefits of rapid disease control, health authorities should consider investing in a better implementation of intensive treatment regimens based on combinations of classical DMARDs and glucocorticoids.

Immunoglobulin D multiple myeloma: response to therapy, survival, and prognostic factors in 75 patients

BackgroundTo analyze the clinical features, outcomes including efficacy of treatment, and prognostic factors of patients with immunoglobulin D multiple myeloma (IgD MM). Design and methodsSeventy-five patients diagnosed with IgD MM were selected from the Korean Myeloma Registry database (www.myeloma.or.kr). ResultsMedian age was 57 years and the main presenting features were bone pain (77%). Renal function impairment and hypercalcemia were present in 40 (53%) and 20 (27%) patients. Sixty-seven patients (89%) had lambda light chains. Forty-eight patients (64%) were of stage III by International Staging System. Twenty-six patients (53%) had chromosomal abnormalities mostly by conventional cytogenetics. Thirty-nine patients (54%) were treated with vincristine, adriamycin, and dexamethasone chemotherapy; the overall response rate (ORR) of 56%. Sixteen patients (22%) received first-line chemotherapy including new drugs (bortezomib or thalidomide), with an ORR of 81%. At a median follow-up time of 28.6 months, median overall survival (OS) was 18.5 months. Age, extramedullary plasmacytoma, del(13) or hypoploidy, serum β2 microglobulin level, and platelet count were significant prognostic factors for OS. ConclusionsIgD MM is an aggressive disease that is usually detected at an advanced stage. Despite a positive initial response, survival after relapse was dismal. Intensive treatment strategies before and following stem cell transplantation may improve outcomes in younger patients.

Hypoglycemia in Type 2 Diabetes—Consequences and Risk Assessment

Although hypoglycemia has traditionally been considered a significant complication of the treatment of type 1 diabetes, the greater incidence of type 2 diabetes compared with type 1, the intensive treatment strategies currently employed, and the longer life expectancy of patients with diabetes, give rise to a large number of type 2 patients at risk for hypoglycemia. This number is likely to rise in an aging population with the increasing use of insulin to treat diabetes. The highest incidence of hypoglycemia is seen in older patients with poor glycemic control and is associated with the use of antidiabetic agents that increase blood insulin concentrations independently of blood glucose concentration (oral antidiabetic drugs or exogenous insulin). Hypoglycemia has a substantial clinical impact in terms of mortality, morbidity, and quality of life. The economic impact of severe hypoglycemic events owing to direct hospital costs and the indirect costs of the inability to work are considerable. Furthermore, both patients’ and physicians’ fear of hypoglycemia reduces adherence to therapeutic regimens and limits the ability of current diabetes medications to achieve the level of glycemic control required to prevent disease progression. Newer therapies and improvements in patient education may help patients achieve improved glucose control by safely reducing glycosylated hemoglobin (HbA1c) with a lower risk of hypoglycemia.

Cladribine Plus Rituximab Is An Effective Therapy for Newly Diagnosed Mantle Cell Lymphoma

AbstractAbstract 4910 Background:Mantle cell lymphoma (MCL) is a B-cell non-Hodgkin lymphoma that is incurable with standard chemotherapy and remains a therapeutic challenge. Despite improved outcomes in MCL there is no consensus on the best initial treatment. Options vary from aggressive treatment strategies that incorporate multi-agent induction chemotherapy and consolidative transplant to less intensive treatment strategies that utilize alkylators, purine nucleoside analogues, and the monoclonal antibody rituximab. Although, higher response rates have been seen with aggressive approaches, their impact on overall survival is not yet fully appreciated and many patients are not candidates for such approaches. Thus, finding less intensive induction regimens is imperative. The combination of rituximab plus cladribine has shown activity across a number of B-cell malignancies and the NCCN treatment guidelines currently include this regimen for the initial treatment of MCL; noting that there are few data available to substantiate this recommendation. The largest prospective experience (n=29) with R-cladribine for the initial treatment of MCL comes from the North Central Cancer Group. They reported an overall response rate (ORR) of 66% with a 52% complete remission (CR) rate and a 2 year progression free survival (PFS) of 43%. Given its therapeutic potential and increasing popularity, more data are needed to verify the benefits of the R-cladribine regimen. Therefore, to explore the role of R-cladribine in the treatment of newly diagnosed MCL, we performed a retrospective chart review of patients with newly diagnosed MCL treated with R-cladribine. Methods:We reviewed the charts of 31 patients with newly diagnosed MCL initially seen at two university hospitals and at an associated VA that were treated with R-cladribine. One patient had been previously treated with 2 cycles of R-CHOP;, all other patients were untreated. All patients had measurable disease and follow up imaging (CT and/or PET/CT scans) before and at the completion of therapy. Post treatment bone marrow biopsies were not available for all patients. Chemotherapy included: cladribine 5mg/m2 given over two hours on days 1–5; and rituximab given on days 1, 8, 15, and 22 with the first cycle and then on day 1 with subsequent cycles. Each cycle was 28 days for up to a total of 6 cycles. Patients with an initial response received maintenance rituximab. Results:The median age of our cohort was 67 years (48-86) with 42% of patients ≥ 65 years. All patients had advanced stage disease (stage ≥ 3) and the majority of patients had poor risk disease. For example, 20/31 (65%) of patients had high FLIPI (≥ 3) and11/31 (37%) had high MIPI (≥ 6). Of the 24 patients in whom beta2-microglobulin was available, 11 (46%) had levels ≥ 3.5 mg/L. The overall response rate (ORR) was 87% with 19/31(61%) of patients achieving a complete remission (CR/CRu). At a median follow up of 21.5 months (2-85 months) the 2 year PFS rate is 65% and the OS rate is 74%. For those subjects achieving a CR/CRu with a median follow up of 23 months, 1/19 (5.3%) has relapsed. No significant trends were seen regarding response rate and pre-treatment disease defining parameters including Ki67, beta2-microglobulin, FLIPI, or MIPI. However, CR was associated with improved survival (p = <.0001) while high MIPI was associated with worse survival (p=0.0317). There was one toxic death (neutropenic sepsis) related to treatment. Conclusion:The combination of rituximab plus cladribine appears to be an effective initial therapy in MCL. The higher response rates seen in this series may be the result of patient selection and/or increased rituximab exposure. Rituximab maintenance may also be an important component of ongoing disease control in responding patients. These data support the ongoing evaluation of rituximab plus cladribine in combination with novel agents. Prospective single arm studies incorporating R-cladribine with other novel agents such as vorinostat, bortezomib, or temsirolimus are ongoing. Disclosures:No relevant conflicts of interest to declare.

Mimetic Peptide to CDK Inhibitor p16 INK4a Induces Cell Death In Mantle Cell Lymphoma Cells: A New Strategy to Eradicate Minimal Residual Disease

AbstractAbstract 3921Autologous stem cell transplantation (ASCT) is an effective treatment strategy for Mantle Cell Lymphoma (MCL) that has been shown to improve disease free survival. However, data from recent trials suggest that the presence of minimal residual disease (MRD) contributes to relapse following current intensive treatment strategies, including ASCT. Thus, we sought to test a highly selective approach to eradication of MRD in stem cell collections from MCL patients using targeted small peptides that disrupt the aberrant cyclin/CDKs interactions that are involved in the pathogenesis of MCL. In the current study, the efficacy of a mimetic peptide to the CDK inhibitor p16INK4a to eliminate MRD was tested. Using (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) (MTS) cell viability assays, we demonstrated that a transducible TAT-p16 mimetic peptide was able to induce cell death in the MCL cell line, Jeko-1, in a dose and time-dependent fashion (see Figure). A TAT-p16 mimetic was able to induce cell death in approximately 60% of Jeko-1 cells after 4 hours of incubation, and approximately 80% of Jeko-1 cells at 24 hours. In contrast, the same dose of TAT-p16 mimetic had no effect on cell survival when it was incubated with CD34+ rich apheresis samples from healthy donors. Furthermore, CFU-GM, BFU-E colony assays showed that there was no toxicity of the TAT-p16 mimetic when compared to untreated cells or cells treated with a control, scrambled TAT-p16 peptide. TAT-p16 mimetic did not impair erythroblast differentiation but induced mild apoptotic cell death in the erythroblast cells. The strategy was further tested using a CD34+ enriched apheresis sample collected from a patient with MCL with documented MRD who had been treated on a clinical trial of ASCT for MCL. Using Real-time quantitative PCR for IgH and BCL1 gene rearrangements, we demonstrated that the TAT-p16 mimetic was able to reduce MRD level by 40% compared with the scrambled TAT-p16 peptide. These data suggest that the use of a peptide-mimetic to p16 selectively and effectively can reduce MRD in MCL cells and in an apheresis (stem cell) sample from a patient with MCL. Treatment with the peptide allowed differentiation of CD34+ progenitor cells. A combinational approach using additional targeted cell cycle regulatory peptides that block p21CIP1/WAF1 and cyclin D2 is being explored to optimize the efficacy of this purging technique. Thus, this novel strategy may be an effective, selective and non-toxic method for eradication of MRD in MCL. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Outcome of Radiotherapy Alone in HPV Associated Oropharyngeal Cancer

Outcome of Radiotherapy Alone in HPV Associated Oropharyngeal Cancer

Peripheral T-cell lymphoma: autologous hematopoietic cell transplantation as first-line therapy

The peripheral T-cell lymphomas (PTCL) are a heterogeneous group of non-Hodgkin's lymphomas associated with an unfavorable prognosis compared with the B-cell non-Hodgkin's lymphomas. The PTCLs are characterized by high remission rates after frontline therapy, but relapse inevitably occurs. The impact of high-dose chemotherapy with autologous hematopoietic cell transplantation (AHCT) as early consolidation therapy will be the focus of this review. In several prospective trials, only PTCL patients with responsive disease after induction chemotherapy proceeded to AHCT. The progression-free survivals ranged from 30% to 40% with low toxicity. The outcomes in retrospective trials appear more favorable but such trials were affected by a selection bias because only chemosensitive patients actually proceeded to AHCT, whereas the prospective studies were intention-to-treat analyses. Most of the published trials demonstrated that prognostic models such as the International Prognostic Index and the Prognostic Index for T-cell lymphoma help predict outcome after AHCT. Current data support the use of AHCT as early consolidation therapy for PTCL patients who are chemosensitive after induction chemotherapy. However, approximately one-third of patients are early induction failures and thus are not able to proceed to AHCT. Additionally, disease relapse remains the leading cause of treatment failure after AHCT, and thus more intensive treatment strategies or better noncross-resistant therapies are greatly needed early in the course of the disease.

Can we achieve true drug-free remission in patients with RA?

Since the introduction of new biologic agents and intensive treatment strategies that aim to tightly control disease activity, clinical remission has become a realistic target in patients with rheumatoid arthritis. Once patients are in continuous remission, however, is it realistic to consider withdrawing DMARD therapy?

Immunoglobulin D Multiple Myeloma: Clinical Presentation, Response to Therapy and Prognostic Factors in 75 Patients; An Analysis of the Korean Multiple Myeloma Working Party (KMMWP).

Abstract 1792Poster Board I-818 PurposeThe primary objective of this study was to analyze the clinical and laboratory characteristics, response to therapy, and survival in patients with IgD multiple myeloma. The secondary objectives were to evaluate the efficacy of treatment, including autologous stem cell transplantation, in these patients. Patients and MethodsRecords of 75 patients with IgD multiple myeloma from 18 institutions were reviewed using the Korean Myeloma Registry (KMR) database (www.myeloma.co.kr). ResultsMedian patient age was 57 years (range, 34∼81 years) and 67% were male. The main presenting features were bone pain (77%) and fatigue (77%). Thirty patients (40%) had ECOG PS ≥ 2, and 71 (94%) had ≥1 lytic bone lesions. Renal function impairment (sCr level ≥2 mg/dL) and hypercalcemia (sCa level ≥12 mg/dL) were present in 53% and 27% of patients, respectively. Median serum M protein level was 1.4 g/dL, and 89% of patients had lambda light chains. Forty-nine patients (65%) were stage III by the ISS and 92% were stage III by DSS. Forty-nine patients were assessable for chromosomal analysis, 46 by conventional cytogenetics and 3 by FISH analysis. Of these, 23 patients (47%) had chromosomal abnormalities associated with poor prognosis. Thirty-nine patients (52%) were treated with VAD chemotherapy; the 36 patients assessable for response had an objective response rate of 59%. Eighteen patients (24%) received first-line combination chemotherapy including new drugs (bortezomib or thalidomide) and their objective response rate was 88%. At a median follow up of 28.6 months for the surviving patients, the median OS was 18.5 months and median PFS was 10.4 months. Multivariate analysis showed that age ' 65 (vs > 65), absence of extramedullary plasmacytoma, absence of del(13) or hypoploidy and serum beta-2 microglobulin level <8.0 mg/dL (vs ≥ 8.0mg/dL) were significant prognostic factors for OS. Thirty-four patients (45%) underwent SCT, 32 as part of their initial therapy. For patients who received SCT after complete or partial response to initial therapy, the median OS was 30 months. ConclusionIgD multiple myeloma is an aggressive disease that is usually detected at an advanced stage. Despite initial response, survival after relapse is dismal. Intensive treatment strategies to induce high quality responses before SCT may improve outcomes in younger patients. DisclosuresSuh:Janssen Korea: Research Funding.

The role of biomarkers in the management of patients with rheumatoid arthritis

In recent years, patient outcomes have improved dramatically with the availability of effective treatments for the management of rheumatoid arthritis (RA). RA, however, is a heterogeneous disease with variable disease progression and treatment response. Whereas some patients respond to a single disease-modifying antirheumatic drug, others require more intensive treatment strategies. Assessing disease severity at diagnosis and monitoring disease activity on an individual level would be a more accurate way of tailoring therapy, ensuring optimal treatment for those at greatest risk of disease progression, long-term disability, and joint damage without unnecessary overtreatment. Assessment of disease activity and severity is currently based on a combination of clinical and laboratory parameters that aid treatment decisions. Use of biomarkers may provide a more accurate means of objectively assessing the disease. This article reviews the role of biomarkers in the management of RA.

GLI1 Is a Direct Transcriptional Target of EWS-FLI1 Oncoprotein

Ewing sarcoma family of tumors (ESFT) is an undifferentiated neoplasm of the bone and soft tissue. ESFT is characterized by a specific chromosomal translocation occurring between chromosome 22 and (in most cases) chromosome 11, which generates an aberrant transcription factor, EWS-FLI1. The function of EWS-FLI1 is essential for the maintenance of ESFT cell survival and tumorigenesis. The Hedgehog pathway is activated in several cancers. Oncogenic potential of the Hedgehog pathway is mediated by increasing the activity of the GLI family of transcription factors. Recent evidence suggests that EWS-FLI1 increases expression of GLI1 by an unknown mechanism. Our data from chromatin immunoprecipitation and promoter reporter studies indicated GLI1 as a direct transcriptional target of EWS-FLI1. Expression of EWS-FLI1 in non-ESFT cells increased GLI1 expression and GLI-dependent transcription. We also detected high levels of GLI1 protein in ESFT cell lines. Pharmacological inhibition of GLI1 protein function decreased proliferation and soft agar colony formation of ESFT cells. Our results establish GLI1 as a direct transcriptional target of EWS-FLI1 and suggest a potential role for GLI1 in ESFT tumorigenesis.

Progress in Defining and Treating High-Risk Neuroblastoma: Lessons From the Bench and Bedside

Progress in Defining and Treating High-Risk Neuroblastoma: Lessons From the Bench and Bedside

Medical Management of Hyperglycemia in Type 2 Diabetes: A Consensus Algorithm for the Initiation and Adjustment of Therapy

The consensus algorithm for the medical management of type 2 diabetes was published in August 2006 with the expectation that it would be updated, based on the availability of new interventions and new evidence to establish their clinical role. The authors continue to endorse the principles used to develop the algorithm and its major features. We are sensitive to the risks of changing the algorithm cavalierly or too frequently, without compelling new information. An update to the consensus algorithm published in January 2008 specifically addressed safety issues surrounding the thiazolidinediones. In this revision, we focus on the new classes of medications that now have more clinical data and experience. Diabetes Care 32:193–203, 2009 The epidemic of type 2 diabetes and the recognition that achieving specific glycemic goals can substantially reduce morbidity have made the effective treatment of hyperglycemia a top priority.1–3 While the management of hyperglycemia, the hallmark metabolic abnormality associated with type 2 diabetes, has historically taken center stage in the treatment of diabetes, therapies directed at other coincident features, such as dyslipidemia, hypertension, hypercoagulability, obesity, and insulin resistance, have also been a major focus of research and therapy. Maintaining glycemic levels as close to the nondiabetic range as possible has been demonstrated to have a powerful beneficial effect on diabetes-specific microvascular complications, including retinopathy, nephropathy, and neuropathy, in the setting of type 1 diabetes;4,5 in type 2 diabetes, more intensive treatment strategies have likewise been demonstrated to reduce microvascular complications.6–8 Intensive glycemic management resulting in lower A1C levels has also been shown to have a beneficial effect on cardiovascular disease (CVD) complications in type 1 diabetes;9,10 however, current studies have failed to demonstrate a beneficial effect of intensive diabetes therapy on CVD in type 2 diabetes. …

Management of Wilms′ tumor: NWTS vs SIOP

With the availability of several protocols in the management of Wilms' tumor, there is dilemma in the minds of the treating oncologists or pediatric onco-surgeons as to whether the child should receive upfront chemotherapy or should be operated upon primarily. It is necessary for us to understand why do we follow either of the protocols, NWTS which follows the upfront surgery principle or the SIOP which follows the upfront chemotherapy principle in all stages of the disease. While deciding which protocol to follow, it is imperative to know the pros and cons of the treatment strategies and also to study the outcome patterns in both the treatment regimes which is what this article highlights. In an attempt to compare all the differences in both the major protocols, it was realized that most of our patients in the Indian scenario present with advanced disease and thus poorer outcomes if intensive and appropriate treatment strategies are not utilized. Hence, it is imperative that we should study our own patients through the Indian Wilms' tumor study group and adopt the policies which improve the overall event free survival on a nationwide basis.

Long-Term Clinical Outcome in Children with Very Severe Aplastic Anemia

Introduction: The clinical course of pediatric patients with severe aplastic anemia (SAA) treated with immunosuppressive therapy (IST) or hematopoietic cell transplantation (HCT) is well known. However, reports on the course and prognosis of patients with very severe aplastic anemia (vSAA) are few. Here, we report on the characteristics and outcome of children with vSAA.Methods: We reviewed the medical records of patients diagnosed with vSAA at the Department of Pediatrics, St. Mary's Hospital, The Catholic University of Korea between January, 1995 to December, 2007. We analyzed the clinical characteristics of the patients at diagnosis, and the effects of IST, HSCT and other supportive treatment measures on patient outcome.Results: Forty three patients were diagnosed with vSAA during the study period, of whom 9 received supportive treatment measures only, 21 received IST consisting of cyclosporine A and either ATG or ALG, and 15 underwent HCT (including 2 patients who showed no response to initial IST). Of the 9 children who received supportive measures only, one patient recovered spontaneously and is surviving event-free for 22 months, 6 patients died from either severe infection or bleeding from 1 to 10 months after diagnosis (median 5 months), and the other two children are continuing to receive supportive transfusions. Of the patients with IST, two children showed a complete response (10.5%), 6 patients showed a partial response (31.6%), and eleven failed to respond (57.9%). Of the 11 patients who did not respond, 8 children died from infection or bleeding within 9 months after IST respectively, 2 patients were lost to follow-up, and 1 patient is receiving supportive transfusions. Of the 8 patients who showed a response, 2 have shown relapse and are being maintained with transfusions. Of the 15 HCT's, 12 were from HLA-matched sibling donors and 3 were from matched unrelated donors. Except for the 2 patients who died from serious infections at 5 and 9 months post-HSCT respectively, all are currently surviving disease-free. The 10-year survival of the patients who received supportive measures only, IST, or HCT is 33.3±15.7%, 47.4±14.0 and 86.7±8.8% respectively (P=0.009).Conclusion: As with SAA, HCT is the best treatment option for vSAA. If IST is undertaken, measures should be undertaken to prevent death from early infection. With only supportive care, median survival approximates only 6 months, calling for more intensive treatment strategies such as IST or HCT in the care of vSAA patients.

VcR-CVAD Produces a High Complete Response Rate in Untreated Mantle Cell Lymphoma: A Phase II Study from the Wisconsin Oncology Network

Introduction: There is no standard treatment for Mantle cell lymphoma (MCL). Intensive treatment strategies such as conventional R-hyperCVAD with alternating R-cytarabine/methotrexate or autologous stem cell transplant appear to improve PFS but the effect on OS is unclear. In addition, approximately 50% of newly diagnosed patients are not candidates for intensive therapies. Novel treatment strategies are needed. We have published the results of a study using a modified R-hyperCVAD induction followed by maintenance rituximab (Kahl et al, Ann Oncol 2006). This induction strategy yielded a complete response (CR) rate of 64% and the entire treatment program yielded a median PFS of 37 months. Bortezomib (Velcade) has demonstrated promising activity in relapsed MCL (Fisher et al, J Clin Onc, 2006). We hypothesized that the incorporation of Velcade (Vc) into the induction regimen would improve the CR rate. The new regimen, VcRCVAD, was tested for safety and efficacy in a phase II study at the University of Wisconsin and within the Wisconsin Oncology Network.Methods: Eligible patients had histologically confirmed mantle cell lymphoma, PS 0–2, and adequate end organ function. The final treatment plan included: Velcade 1.3 mg/m2 days 1 and 4, rituximab 375 mg/m2 IV day 1, cyclophosphamide 300 mg/m2 IV over 3 hrs q 12 hrs X 6 doses days 1–3, doxorubicin 50 mg/m2 continuous infusion over 48 hrs days 1–2, vincristine 1 mg IV day 3, dexamethasone 40 mg po days 1–4. Due to excessive painful peripheral neuropathy (PN), 2 dose modifications were required during the course of the study. Patients 1–7 received 1.5 mg/m2 Velcade and 2 mg vincristine. Patients 8–14 received 1.3 mg/m2 Velcade and 2 mg vincristine. Patients 15–30 received 1.3 mg/m2 Velcade and 1 mg vincristine. Cycles were repeated every 21 days for 6 cycles and all patients received G-CSF cytokine support. Patients achieving at least a PR receive maintenance rituximab therapy for 5 years.Results: Enrollment is complete and all 30 patients are evaluable for response to VcRCVAD induction. Baseline characteristics include median age 60.5 (48–74), 24M:6F, 26/30 (87%) stage IV, and 12 (40%) low-risk, 8 (27%) int-risk, and 10 (33%) high-risk by MIPI. 3 patients (10%) experienced PD during induction therapy and 27 (90%) responded with 23 CR/CRu (77%) and 4 PR (13%). With a median follow up of approximately 18 months, the 18-month PFS and OS are 73% and 97%, respectively. The major toxicity of this treatment regimen is painful PN and expected hematologic toxicity. 5/7 patients in cohort 1 and 3/7 patients in cohort 2 developed grade 3 painful PN and 1 patient in cohort 2 developed grade 4 painful PN. Only 1/16 patients in the final cohort experienced grade 3 painful PN. All neuropathy eventually improved to ≤ grade 2, but 10 patients require chronic medication for symptom relief. 13/167 (8%) of the treatment cycles were complicated by neutropenic fever/infection. There were no treatment related deaths.Conclusion: The VcR-CVAD induction has produced high overall response (90%) and CR rate (77%) in a very representative MCL patient population. Comparing these data to our previous frontline MCL study, the CR rate appears to be enhanced (77% vs 64%) by the addition of Velcade. Longer follow up is needed before determining if the higher CR rate will translate into an improved PFS and OS. Because of the risk for painful PN, caution must be exercised when using vincristine and Velcade in combination. The MTD for this combination was 1 mg vincristine and 1.3 mg/m2 Velcade. The encouraging complete response rate provided the rationale for ECOG study E1405, which is testing the safety and efficacy of this induction regimen in a cooperative group setting.

Intensive treatment strategies may not provide superior outcomes in mantle cell lymphoma: overall survival exceeding 7 years with standard therapies

BackgroundReported median overall survival (OS) in patients with mantle cell lymphoma (MCL) has been reported to be just 3–4 years. As a consequence, first-line treatment has become more aggressive. Single-center studies with R-Hyper-CVAD and/or autologous stem-cell transplant (ASCT) have produced 3-year OS rates >80%, prompting many to adopt their use. We evaluated outcomes from a single-center cohort managed in a more traditional fashion. MethodsWe identified patients with MCL evaluated at Weill Cornell Medical Center since 1997, and included those with known date of diagnosis. An online social security database was used to verify survival. ResultsWe identified 181 patients with MCL, and date of diagnosis could be determined in 111. Three-year OS from diagnosis was 86% [95% confidence interval (CI) 78% to 92%]. Median OS was 7.1 years (95% CI 63–98 months). Adequate information on therapy was available for 75 patients. Only five were treated upfront with (R)-Hyper-CVAD or ASCT while an additional four patients received one of these regimens subsequently. Treatment type had no significant effect on OS. ConclusionOutcomes with standard approaches can yield similar survival to that achieved with more intensive approaches. Biases may account for the perceived superiority of aggressive strategies.