Fatal hepatorenal failure and thrombocytopenia with SU5416, a vascular endothelial growth factor Flk-1 receptor inhibitor, in AIDS-Kaposi's sarcoma.
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Acquired Immunodeficiency Syndrome↗
Biomedical subjects
Ariela Noy
Publications and source records attributed to Ariela Noy.
Update in HIV lymphoma.
PURPOSE OF REVIEW: Despite the control of HIV infection in industrialized nations, individuals infected with HIV remain at increased risk of malignancies. Lymphoma is the most common HIV-associated malignancy in these countries. This review summarizes progress from January 2005 to March 2006. RECENT FINDINGS: Investigators continue to demonstrate that HIV-associated non-Hodgkin's lymphoma remains a significant problem, even in the era of highly active antiretroviral therapy. The majority of work has been in diffuse large B-cell lymphoma, with infusional therapy remaining promising, and rituximab an area of investigation. The latter improves complete response rates, but is associated with an increased incidence of infections. Biological insights have been gained into the spectrum of HIV-associated non-Hodgkin's lymphoma and Hodgkin's disease, and include further work on virological co-infections. SUMMARY: The outcome for individuals infected with HIV and developing non-Hodgkin's lymphoma and Hodgkin's disease continues to improve as insights into the pathophysiology and treatment advance.
Anti-Retroviral Agents↗
Developing a cancer-specific geriatric assessment: a feasibility study.
BACKGROUND: As the U.S. population ages, there is an emerging need to characterize the "functional age" of older patients with cancer to tailor treatment decisions and stratify outcomes based on factors other than chronologic age. The goals of the current study were to develop a brief, but comprehensive, primarily self-administered cancer-specific geriatric assessment measure and to determine its feasibility as measured by 1) the percentage of patients able to complete the measure on their own, 2) the length of time to complete, and 3) patient satisfaction with the measure. METHODS: The geriatric and oncology literature was reviewed to choose validated measures of geriatric assessment across the following domains: functional status, comorbidity, cognition, psychological status, social functioning and support, and nutritional status. Criteria applied to geriatric assessment measurements included reliability, validity, brevity, and ability to self-administer. The measure was administered to patients with breast carcinoma, lung carcinoma, colorectal carcinoma, or lymphoma who were fluent in English and receiving chemotherapy at Memorial Sloan-Kettering Cancer Center (New York, NY) or the University of Chicago (Chicago, IL). RESULTS: The instrument was completed by 43 patients (mean age, 74 yrs; range, 65-87 yrs). The majority had AJCC Stage IV disease (68%). The mean time to completion of the assessment was 27 minutes (range, 8-45 mins). Most patients were able to complete the self-administered portion of the assessment without assistance (78%) and were satisfied with the questionnaire length (90%). There was no association noted between age (P = 0.56) or educational level (P = 0.99) and the ability to complete the assessment without assistance. CONCLUSIONS: In this cohort, this brief but comprehensive geriatric assessment could be completed by the majority of patients without assistance. Prospective trials of its generalizability, reliability, and validity are justified.
Activities of Daily Living↗
Gastric mucosa-associated lymphoid tissue lymphoma detected by clonotypic polymerase chain reaction despite continuous pathologic remission induced by involved-field radiotherapy.
PURPOSE: Gastric mucosa-associated lymphoid tissue (MALT) lymphoma is indolent and often associated with Helicobacter pylori bacterial infection. H pylori-independent MALT develops either in the absence of the bacteria or persists after bacterial eradication. We have previously demonstrated long-term pathologic remission after involved-field radiotherapy therapy (IFRT). We determined molecular remission status by clonotypic polymerase chain reaction (PCR). PATIENTS AND METHODS: Twenty-four consecutive patients with stage I to IIE gastric MALT lymphoma who obtained a pathologic remission after IFRT alone were evaluated. All had at least two follow-up endoscopic gastroduodenal biopsies at Memorial Sloan-Kettering Cancer Center. IFRT median dose was 30 Gy (range, 28.5 to 43.5 Gy). Post-treatment biopsies were subjected to semi-nested clonotypic PCR. RESULTS: All patients obtained a complete response based on routine immunohistochemical pathologic analysis of random post-treatment gastric biopsies. Median follow-up from completion of IFRT was 63 months (range, 19 to 117 months). Event-free survival was 96%; 23 of 34 patients remained in clinical and pathologic complete remission. Baseline DNA extraction yielded 17 clone-specific primer pairs. At the first follow-up test, 14 of 17 pairs were PCR positive. Eight remained persistently positive; and one was persistently negative. Others were intermittently positive. CONCLUSION: Despite sustained biopsy-proven remissions for as long as 117 months after radiation, the vast majority of patients remain positive by clonotypic PCR. This suggests that the malignant clone is present but missing either an internal or external signal essential to the cancer phenotype. One possibility is that radiation eradicates the polyclonal H pylori-specific T cells eliminating critical local factors necessary for proliferation of the monoclonal B cells.
Clone Cells↗
Intensity of 18fluorodeoxyglucose uptake in positron emission tomography distinguishes between indolent and aggressive non-Hodgkin's lymphoma.
PURPOSE: (18)Fluorodeoxyglucose positron emission tomography (FDG PET) is widely used for the staging of lymphoma. We investigated whether the intensity of tumor FDG uptake could differentiate between indolent and aggressive disease. MATERIALS AND METHODS: PET studies of 97 patients with non-Hodgkin's lymphoma who were untreated or had relapsed and/or persistent disease and had not received treatment within the last 6 months were analyzed, and the highest standardized uptake value (SUV) per study was recorded. Correlations were made with histopathology. RESULTS: FDG uptake was lower in indolent than in aggressive lymphoma for patients with new (SUV, 7.0 +/- 3.1 v 19.6 +/- 9.3; P < .01) and relapsed (SUV, 6.3 +/- 2.7 v 18.1 +/- 10.9; P = .04) disease. Despite overlap between indolent and aggressive disease in the low SUV range (indolent, 2.3 to 13.0; aggressive, 3.2 to 43.0), all cases of indolent lymphoma had an SUV 10 excluded indolent lymphoma with a specificity of 81%. With a higher cutoff for the SUV, the specificity would have been higher. CONCLUSION: FDG uptake is lower in indolent than in aggressive lymphoma. Patients with NHL and SUV > 10 have a high likelihood for aggressive disease. This information may be helpful if there is discordance between biopsy and clinical behavior.
Adolescent↗
R-CHOP-14 in patients with diffuse large B-cell lymphoma: feasibility and preliminary efficacy.
Treatment of diffuse large B-cell lymphoma (DLBCL) with CHOP-21 (cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, vincristine 1.4 mg/m2, prednisone 100 mg for 5 days every 21 days) results in long-term remission in approximately 45% of patients. Recent phase III trials have demonstrated improved survival by modifying CHOP either through adding rituximab or shortening the time between cycles to 14 days. These studies prompted our institution to treat newly diagnosed patients with DLBCL refusing or not eligible for protocol-based therapy with R-CHOP-14. In this single-institution retrospective analysis, we report our results with this regimen. Forty-nine patients with newly diagnosed DLBCL and ineligible or refusing protocol-based therapy were retrospectively identified. Patients were treated with 6-8 cycles of R-CHOP-14 given with filgrastim and prophylactic antibiotics. The main toxicities with R-CHOP-14 were hematological and neurological and were not unexpected. There were no treatment-related deaths. Patients received 90% of planned cytotoxic drug density. The complete remission/complete remission uncertain (CR/CRu) rate was 82.2%. At a median follow-up of 24 months, the event-free survival was 80% and overall survival 90%. These results demonstrate R-CHOP-14 can be given to patients safely and short-term results regarding survival are promising. Whether adding rituximab and increasing dose intensity improves survival over either alone will require randomized studies.
Antibodies, Monoclonal↗
Primary mediastinal large B-cell lymphoma: optimal therapy and prognostic factor analysis in 141 consecutive patients treated at Memorial Sloan Kettering from 1980 to 1999.
Primary mediastinal large B-cell lymphoma (PMLBL) is a distinct clinicopathological entity with unclear prognostic factors and optimal treatment approach. To elucidate an optimal treatment and identify predictive factors, a retrospective analysis of 141 consecutive patients was undertaken. Patients received cyclophosphamide, hydroxydaunomycin, Oncovin, prednisone (CHOP)-like therapy, the non-Hodgkin lymphoma (NHL)-15 regimen or upfront autologous stem cell transplantation (ASCT) on Institutional Review Board approved trials or according to the institutional guidelines. Evaluation included lactate dehydrogenase, International Prognostic Index (IPI) assessment, computed tomography scan and gallium imaging. With a median follow-up of 10.9 years, event-free survival (EFS) and overall survival (OS) was 50% and 66% respectively. EFS/OS for CHOP/CHOP-like, NHL-15 and upfront ASCT was 34/51%, 60/84% and 60/78% respectively. CHOP/CHOP-like regimens had inferior EFS and OS versus NHL-15 or upfront ASCT (P < 0.001). A total of 23% of patients received radiotherapy. Multivariate analysis revealed the following outcome predictors: for EFS, greater than or equal to two extranodal sites and initial therapy received (NHL-15 or upfront ASCT); for OS, only initial therapy with NHL-15. We conclude: (i) dose-dense chemotherapy with NHL-15 may be superior to CHOP for PMLBL; (ii) The impact of consolidative radiotherapy requires randomised controlled trials; (iii) The age-adjusted IPI did not predict survival in this analysis; (iv) high-dose chemotherapy/ASCT should be reserved for upfront anthracycline-based therapy failure or in clinical trials for high-risk patients.
Adolescent↗
Angiogenesis inhibitor IM862 is ineffective against AIDS-Kaposi's sarcoma in a phase III trial, but demonstrates sustained, potent effect of highly active antiretroviral therapy: from the AIDS Malignancy Consortium and IM862 Study Team.
PURPOSE: IM862 is a synthetic dipeptide (L-glutamine L-tryptophan) with in vitro and in vivo antiangiogenic properties. Phase I/II studies showed minimal toxicity and a response rate of 36% in AIDS-Kaposi's sarcoma. We report a 24-week, randomized, double-blinded, placebo-controlled phase III trial with the phase II dose, 5 mg intranasally every other day. PATIENTS AND METHODS: Two hundred two HIV-positive patients were enrolled, 104 on IM862 and 98 on placebo. RESULTS: Baseline characteristics were comparable except current antiretroviral therapy: 88% versus 96% (IM862 v placebo group; P = .042). The median treatment durations were 19.5 versus 24 weeks (IM862 v placebo). No significant difference was detected in response rate (IM862, 23%; 95% CI, 15% to 32% v placebo, 21%; 95% CI, 14% to 31%; P = .46), time to response (8.5 weeks v 14 weeks; P = .024), or duration of response. However, IM862 was associated with both a shorter time to response (8.5 weeks v 14 weeks; P = .024) and shorter median time to progression (16 weeks, 95% CI, 13 to 27 weeks v 35 weeks, 95% CI, 26 to 114 weeks; P = .012). CONCLUSION: Despite promising phase I and phase II studies, IM862 5 mg every other day was not superior to placebo and may accelerate time to progression. Highly active antiretroviral therapy alone was associated with a substantial rate of sustained tumor response and may have contributed to prior estimates of IM862 response. Therapeutic trials for AIDS-Kaposi's sarcoma must account for ongoing immune reconstitution in the setting of concurrent highly active antiretroviral therapy that may confound estimates of therapeutic activity.
AIDS-Related Opportunistic Infections↗
Results of a prospective randomized clinical trial of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) followed by radiation therapy (RT) versus ABVD alone for stages I, II, and IIIA nonbulky Hodgkin disease.
To determine whether combined modality therapy (CMT) is superior to chemotherapy (CT) alone, 152 untreated Hodgkin disease patients with clinical stages (CSs) IA, IB, IIA, IIB, and IIIA without bulk disease were prospectively randomized to 6 cycles of doxorubicin, bleomycin, vinblastine, dacarbazine (ABVD) alone or 6 cycles of ABVD followed by radiation therapy (RT) (3600 cGy: involved field for 11 patients, modified extended field for the rest). Of 76 patients randomized to receive RT, 65 actually received it, and 11 did not (4 progressed, 1 had bleomycin toxicity, 6 refused). For ABVD + RT, the complete remission (CR) percentage was 94% and no major response, 6%. For ABVD alone, 94% achieved a CR; 1.5%, a partial response (PR); and 4.5%, no major response. At 60 months CR duration, freedom from progression (FFP), and overall survival (OS) for ABVD + RT versus ABVD alone are 91% versus 87% (P = .61), 86% versus 81% (P = .61), and 97% versus 90% (P = .08), respectively (log-rank). The 95% confidence intervals for CR duration, FFP, and OS differences at 5 years were -8% to 15%, -8% to 18%, and -4% to 12%, respectively. Although significant differences were not seen, it is possible that a benefit in outcome of less than 20% for CMT might be seen in a larger trial.
Adolescent↗
Rituximab and ICE as second-line therapy before autologous stem cell transplantation for relapsed or primary refractory diffuse large B-cell lymphoma.
Patients with relapsed or primary refractory diffuse large B-cell lymphoma (DLBCL) who achieve complete response (CR) before autologous stem cell transplantation (ASCT) generally have better outcomes than those who achieve only partial response (PR). We investigated whether adding rituximab to the ifosfamide-carboplatin-etoposide (ICE) chemotherapy regimen (RICE) could increase the CR rate of patients with DLBCL under consideration for ASCT. Thirty-six eligible patients were treated with RICE, and 34 received all 3 planned cycles. The CR rate was 53%, significantly better than the 27% CR rate (P =.01) achieved among 147 similar consecutive historical control patients with DLBCL treated with ICE; the PR rate was 25%. Febrile neutropenia was the most frequent grade 3 or 4 nonhematologic toxicity; it occurred in 7.5% of delivered cycles. No patient had RICE-related toxicity that precluded ASCT. The median number of CD34(+) cells per kilogram mobilized was 6.3 x 10(6). Progression-free survival rates of patients who underwent transplantation after RICE were marginally better than those of 95 consecutive historical control patients who underwent transplantation after ICE (54% vs 43% at 2 years; P =.25). RICE appears to induce very high CR rates in patients with relapsed and refractory DLBCL; however, further studies are necessary to determine whether this treatment regimen will improve outcomes after ASCT.
Adolescent↗
Update in HIV-associated lymphoma.
PURPOSE OF REVIEW: Infection with human immunodeficiency virus (HIV) is associated with an increased risk of non-Hodgkin lymphoma and Hodgkin disease. This review summarizes developments within the past 18 months. RECENT FINDINGS: Investigators continue to demonstrate that many standard therapies similar to those used in the non-HIV- infected population may be used in the HAART era for patients infected with HIV. Biologic differences do exist, however, and not all treatments and outcomes are directly translatable. Some treatments, such as rituximab in combination with CHOP, may have unforeseen toxicity. Nonetheless, high-dose therapy does appear feasible and may offer curative therapy for those with refractory and relapsed disease. SUMMARY: HIV-infected persons appear to benefit from most, but not all standard treatments for lymphoma.
Humans↗
Adverse prognostic significance of CD20 positive Reed-Sternberg cells in classical Hodgkin's disease.
The prognostic significance of CD20 positive classical Hodgkin's disease (cHD) is uncertain. All cHD cases referred to the Memorial Sloan-Kettering Cancer Center (MSKCC) were retrospectively identified (5/92-11/00); the samples were immunostained, and clinical data ascertained. Cases were re-reviewed without knowledge of clinical outcome. Univariate and multivariate analyses were performed 248 patients had cHD: 28 CD20(+) (11%); 220 CD20(-). All clinical characteristics were comparable except haemoglobin level at presentation. With a median follow-up of 29.2 months, significant prognostic factors in multivariate analysis were: CD20 positivity, elevated white blood cell count (WBC) and low absolute lymphocyte count for time-to treatment failure (TTF); and for overall survival (OS), CD20 positivity, elevated WBC count, bone marrow involvement and age >/=45 years. TTF was significantly poorer for ABVD-treated patients with CD20(+) cHD as compared with CD20(-) cHD. Among 167 patients treated at MSKCC, both TTF (P < 0.0001) and OS (P = 0.017) were significantly decreased in CD20(+) patients as compared with CD20(-) cHD. CD20(+) cHD is a poor prognostic factor for TTF and OS. All cHD cases should be immunophenotyped for CD20. A large prospective trial is needed to confirm these findings.
Adolescent↗
Intensive chemotherapy with cyclophosphamide, doxorubicin, high-dose methotrexate/ifosfamide, etoposide, and high-dose cytarabine (CODOX-M/IVAC) for human immunodeficiency virus-associated Burkitt lymphoma.
BACKGROUND: In the era of highly active antiretroviral therapy (HAART), standard-dose chemotherapy for human immunodeficiency virus (HIV)-associated diffuse large B-cell lymphoma is becoming the standard of care. In contrast, the safety and efficacy of intensive regimens have not been established for Burkitt lymphoma (BL), a highly aggressive lymphoma for which moderate-dose chemotherapy is substandard in the HIV-negative population. METHODS: To evaluate the feasibility of intensive chemotherapy in HIV-associated BL, the authors retrospectively reviewed 14 HIV-positive adults with BL treated at their center between 1988 and 2000. Eight patients were treated between 1996 and 2000 with cyclophosphamide, doxorubicin, high-dose methotrexate/ifosfamide, etoposide, and high-dose cytarabine (CODOX-M/IVAC), one of the currently preferred intensive-dose chemotherapy regimens for BL. Six received other chemotherapy. Outcomes were compared with those of 24 HIV-negative adult patients with BL who had similar patient characteristics and were treated concomitantly (13 with CODOX-M/IVAC; 11 with other regimens). RESULTS: Of the 14 HIV-positive patients, 63% had a complete response after CODOX-M/IVAC treatment, compared with 67% of patients receiving other chemotherapy. The 2-year event-free survival (EFS) rates were 60% and 60% after CODOX-M/IVAC or other regimens, respectively. Similar outcomes were seen despite the fact that 88% of CODOX-M/IVAC-treated HIV-positive patients had Stage IV disease, compared with one-third of HIV-positive patients treated with other chemotherapy. HIV status did not adversely affect long-term EFS independent of the treatment regimen (P = 0.88). When EFS was evaluated according to chemotherapy regimen independent of HIV status, CODOX-M/IVAC was found to be associated with improved EFS (P = 0.05) in all patients, and particularly those at high risk. HIV-positive patients treated with CODOX-M/IVAC tolerated chemotherapy well with similar rates of myelosuppression and infectious complications as HIV-negative patients. CONCLUSIONS: The current nonrandomized retrospective study suggested that intensive chemotherapy with CODOX-M/IVAC is feasible and well tolerated in HIV-positive adults with BL. In the post-HAART era, intensive chemotherapy such as CODOX-M/IVAC may be appropriate in all adult patients with BL, and especially those with poor prognostic factors, regardless of HIV status.
Adult↗
Age-adjusted International Prognostic Index predicts autologous stem cell transplantation outcome for patients with relapsed or primary refractory diffuse large B-cell lymphoma.
Second-line chemotherapy followed by high-dose therapy (HDT) with autologous stem cell transplantation (ASCT) cures less than half of the patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). Prognostic models capable of predicting outcome are essential. In 3 sequential clinical trials, conducted from January 1993 to August 2000, we treated 150 patients with relapsed or primary refractory DLBCL with ifosfamide, carboplatin, and etoposide (ICE) chemotherapy followed by HDT/ASCT for patients with chemosensitive disease. We evaluated the age-adjusted International Prognostic Index at the initiation of second-line therapy (sAAIPI) as a predictor of progression-free survival (PFS) and overall survival (OS). At a median follow-up of 4 years, the PFS and OS are 28% and 34% by intention to treat and 39% and 45% for only those patients with chemosensitive disease. Three risk groups with different PFS and OS were identified by the sAAIPI: low risk (0 factors), 70% and 74%; intermediate risk (1 factor), 39% and 49%; and high risk (2 or 3 factors), 16% and 18% (P <.001 for both PFS and OS). The sAAIPI also predicts the PFS and OS for patients with ICEchemosensitive disease: low risk, 69% and 83%; intermediate risk, 46% and 55%; and high risk, 25% and 26% (P <.001 PFS and OS). The sAAIPI predicts outcome for patients with relapsed or primary refractory DLBCL in both intent-to-treat and chemosensitive populations. This powerful prognostic instrument should be used to evaluate new treatment approaches and to compare results of different regimens.
Adolescent↗
Update in Kaposi sarcoma.
PURPOSE OF REVIEW: Knowledge of the pathophysiology of Kaposi sarcoma continues to expand and influence our therapeutic approaches. This review summarizes developments within the last 18 to 24 months. RECENT FINDINGS: Pieces of the puzzle as they relate to viral factors-both human herpes virus 8 (HHV-8) and human immunodeficiency virus (HIV)-endothelial cells, host immune factors, and cytokines are described. Recent observations relating to highly active antiretroviral therapy (HAART) and agents under investigation that exploit the developments in pathophysiology are reviewed. SUMMARY: Advances in Kaposi sarcoma pathophysiology are leading to new therapeutic approaches. These will undoubtedly have an impact on other viral and malignant processes as well.
Humans↗
Rituximab for aggressive non-Hodgkin's lymphomas relapsing after or refractory to autologous stem cell transplantation.
PURPOSE: The median survival for aggressive non-Hodgkin's lymphomas relapsing after or refractory to high-dose therapy and autologous stem cell transplantation therapy is 6.2 months. In these cases, there is limited salvageability with the use of conventional therapy. The purpose of this retrospective analysis was to evaluate single-agent rituximab as treatment for aggressive non-Hodgkin's lymphomas in these cases. PATIENTS AND METHODS: Between January 1997 and February 2000, we treated 17 patients with aggressive non-Hodgkin's lymphomas whose disease was refractory to, or relapsed after, autologous stem cell transplantation. Treatment consisted of rituximab, 375 mg/m2 as a single agent for four weekly doses. Thirteen patients had diffuse large B-cell lymphoma, and four patients had mantle cell lymphoma. The median time from autologous stem cell transplantation to relapse was 10 months (range, 2-40 months). The median number of prior therapies, including autologous stem cell transplantation, was three (range, 2-6). RESULTS: The overall response rate to rituximab was 53%, and there were four complete responses and five partial responses. Seven of 13 patients with diffuse large B-cell lymphoma (three complete responses, four partial responses) responded, and two of four patients with mantle cell lymphoma (one complete responses, one partial responses) responded. The median progression-free survival for all responders was 13 months (range, 6-18 months). Four responders (two complete responses, two partial responses) were re-treated with a second course of rituximab for disease recurrence and responded to further antibody therapy. Rituximab was well tolerated with no serious adverse events. DISCUSSION: Rituximab is effective and well-tolerated palliative treatment for aggressive non-Hodgkin's lymphomas that relapse after or is refractory to autologous stem cell transplantation.
Adult↗