Patients with classical Hodgkin lymphoma experiencing disease progression after treatment with brentuximab vedotin have poor outcomes.

BACKGROUND: Brentuximab vedotin (BV) is a key therapeutic agent for patients with relapsed/refractory classical Hodgkin lymphoma (cHL). The outcomes of patients experiencing disease progression after BV are poorly described. PATIENTS AND METHODS: We reviewed our institutional database to identify patients with cHL treated with BV who were either refractory to treatment or experienced disease relapse. We collected clinicopathologic features, treatment details at progression and outcome. RESULTS: One hundred patients met inclusion criteria, with a median age of 32 years (range 18-84) at progression after BV. The median number of treatments before BV was 3 (range 0-9); 71 had prior autologous stem cell transplant. The overall response rate (ORR) to BV was 57%, and the median duration of BV therapy was 3 months (range 1-25). After disease progression post-BV, the most common treatment strategies were investigational agents (n = 30), gemcitabine (n = 15) and bendamustine (n = 12). The cumulative ORR to therapy was 33% (complete response 15%). After a median follow-up of 25 months (range 1-74), the median progression-free (PFS) and overall survival (OS) were 3.5 and 25.2 months, respectively. In multivariate analysis, no factors analyzed were predictive of PFS; age at progression >45 years and serum albumin <40 g/l at disease progression were associated with increased risk of death. Among patients who achieved response to therapy, allogeneic stem cell transplantation was associated with a non-significant trend toward superior OS (P = 0.11). CONCLUSIONS: Patients with BV-resistant cHL have poor outcomes. These data serve as a reference for newer agents active in BV-resistant disease.

Factors influencing outcome in advanced stage, low-grade follicular lymphoma treated at MD Anderson Cancer Center in the rituximab era.

BACKGROUND: The optimal initial therapy of follicular lymphoma (FL) remains unclear. The aims of this study were to compare primary treatment strategies and assess the impact of maintenance rituximab and patterns of treatment failure. PATIENTS AND METHODS: We retrospectively analyzed patients with treatment-naive advanced stage, grade 1-2 FL treated at our center from 2004 to 2014. We included 356 patients treated on clinical trials or standard of care with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP, n = 119); R-CHOP with maintenance (R-CHOP + M, n = 65); bendamustine/rituximab (BR, n = 45); BR with maintenance (BR + M, n = 35); R(2) (n = 94). We compared baseline characteristics, progression-free survival (PFS), overall survival (OS) and analyzed prognostic factors using univariate and multivariate analysis adjusted for treatment. RESULTS: After a median follow-up of 4 years (range 0.2-15.0), the 3-year PFS was 60% [95% confidence interval (CI) 51% to 69%] for R-CHOP, 72% (59% to 82%) for R-CHOP + M, 63% (42% to 78%) for BR, 97% (80% to 100%) for BR + M and 87% (78% to 93%) for R(2). Patients treated with R-chemotherapy had more high-risk features than patients treated with R(2) but, by adjusted multivariate analysis, treatment with R(2) [hazard ratio (HR) 0.39 (0.17-0.89), P = 0.02] was associated with a superior PFS. Eastern Cooperative Oncology Group Performance status of one or more predicted inferior OS. Among patients treated with R-chemotherapy, maintenance was associated with the superior PFS [HR 0.38 (95% CI 0.21-0.68)]. By adjusted multivariate analysis, disease progression within 2 years [HR 5.1 (95% CI 1.57-16.83)] and histologic transformation (HT) [HR 11.05 (95% CI 2.84-42.93)] increased risk of death. CONCLUSION: Induction therapy with R(2) may result in disease control which is comparable with R-chemotherapy. Early disease progression and HT are predictive of inferior survival.

Patients with mantle cell lymphoma failing ibrutinib are unlikely to respond to salvage chemotherapy and have poor outcomes.

BACKGROUND: Although ibrutinib is highly effective in patients with relapsed/refractory mantle cell lymphoma (MCL), a substantial proportion of patients have resistant disease. The subsequent outcomes of such patients are unknown. PATIENTS AND METHODS: We carried out a retrospective review of all patients with MCL treated with ibrutinib at MD Anderson Cancer Center between January 2011 and January 2014 using pharmacy and clinical databases. Patients who had discontinued ibrutinib for any reason were included in the study. RESULTS: We identified 42 patients with MCL who discontinued therapy due to disease progression on treatment (n = 28), toxicity (n = 6), elective stem-cell transplant in remission (n = 4) or withdrawn consent (n = 4). The median age was 69 years, 35 (83%) were male; the median number of prior treatments was 2 (range 1-8) and the median time from initial diagnosis of MCL to commencing ibrutinib was 3.0 (range 0.5-15.5) years. Patients had received a median of 6.5 (range 1-43) cycles of ibrutinib. Among 31 patients who experienced disease progression following ibrutinib and underwent salvage therapy, the overall and complete response rates were 32% and 19%, respectively. After a median follow-up of 10.7 (range 2.4-38.9) months from discontinuation of ibrutinib, the median overall survival (OS) among patients with disease progression was 8.4 months. By univariate analysis, elevated serum lactate dehydrogenase at progression was associated with inferior OS. CONCLUSION: The outcome of patients with MCL who experience disease progression following ibrutinib therapy is poor, with both low response rates to salvage therapy and short duration of responses. Further studies to better understand and overcome ibrutinib resistance are urgently needed.

Use of Screening Tests for Colorectal Cancer Among Gynecologists in Puerto Rico.

OBJECTIVE: To determine the use of screening tests for colorectal cancer (CRC) among Gynecologists in Puerto Rico. This study evaluates the screening practices used by Gynecologists in PR to diagnose CRC and adherence to screening guidelines. METHODS: A self-administered anonymous questionnaire was mailed to 440 practicing gynecologists through the College of Physicians and Surgeons of PR. The questionnaire included general and specific questions. RESULTS: Response rate was 23.2% (102/440). Of this group of gynecologists, 77.5% referred screening patients, while 22.5% did not. The majority (28.4%) use Fecal Occult Blood Test (FOBT) as a first screening test, while 27.5% use Colonoscopy. Screening is started by 49% at age 50. Only 7% stop screening at 75 years and 31% never stop screening. CRC Screening performed by participants were: 35% screen annually, 6% screen 2-3 years, 10% screen every 5 years, 6% screen every 10 years and 6% screen 5-10 years. Data for CRC Screening reveals 7% gynecologists comply with all the guidelines; 49% comply with the recommendations regarding the start screening age and 7% stop screening as per guidelines. CONCLUSION: The recommendations are not followed by most of the gynecologists in PR that participated in the study, Further research should be directed towards the reasons for not complying and how to educatethemedical population to achieve adequate screening in the PR female population.

A randomized trial of a single-dose rasburicase versus five-daily doses in patients at risk for tumor lysis syndrome.

BACKGROUND: Tumor lysis syndrome (TLS) is a life-threatening disorder characterized by hyperuricemia and metabolic derangements. The efficacy of rasburicase, administered daily for 5 days, has been well established. However, the optimal duration of therapy is unknown in adults. PATIENTS AND METHODS: We evaluated the efficacy of rasburicase (0.15 mg/kg) administered as single dose followed by as needed dosing (maximum five doses) versus daily dosing for 5 days in adult patients at risk for TLS. RESULTS: Eighty of the 82 patients enrolled received rasburicase; 40 high risk [median uric acid (UA) 8.5 mg/dl; range, 1.5-19.7] and 40 potential risk (UA = 5.6 mg/dl; range, 2.4-7.4). Seventy-nine patients (99%) experienced normalization in their UA within 4 h after the first dose; 84% to an undetectable level (<0.7 mg/dl). Thirty-nine of 40 (98%) patients in the daily-dose arm and 34 of 40 (85%) patients in single-dose arm showed sustained UA response. Six high-risk patients within the single-dose arm required second dose for UA >7.5 mg/dl. Rasburicase was well tolerated; one patient with glucose-6-phosphate dehydrogenase deficiency developed methemoglobinemia and hemolysis. CONCLUSIONS: Rasburicase is highly effective for prevention and management of hyperuricemia in adults at risk for TLS. Single-dose rasburicase was effective in most patients; only a subset of high-risk patients required a second dose.

Prospective trial of targeted radioimmunotherapy with Y-90 ibritumomab tiuxetan (Zevalin) for front-line treatment of early-stage extranodal indolent ocular adnexal lymphoma.

BACKGROUND: To determine the efficacy and side-effects of (90)Y ibritumomab tiuxetan (Zevalin) as front-line treatment in patients with early-stage extranodal indolent lymphoma of the ocular adnexa (orbit, conjunctiva, or eyelid). PATIENTS AND METHODS: From August 2004 to November 2007, 12 patients with stages I-E extranodal indolent lymphoma of the ocular adnexa were enrolled in a prospective trial of rituximab followed by (90)Y ibritumomab tiuxetan (Zevalin therapeutic regimen). For each patient, clinical examinations and imaging studies were used to document response to therapy using the The International Working Group response criteria. All patients had (111)In ibritumomab tixuetan imaging to confirm expected biodistribution before (90)Y-Zevalin therapy; in addition, three patients had an optional single photon emission computed tomography-computed tomography scan to estimate the absorbed radiation dose to the orbital and ocular tissues. RESULTS: The study included seven women and five men. The median age was 60 years (range 22-79). Nine patients had mucosa-associated lymphoid tissue lymphoma of conjunctiva or orbit; three patients had grades 1-2 follicular lymphoma of orbit. One patient who had been deemed stage I-E initially was found to have another lesion in her deltoid muscle on positron emission tomography 2 weeks after enrollment. She was kept on trial although her disease was reclassified as stage IV due to this single additional (biopsy-proven) site. Ten patients had a complete response and two partial response (PR) within 3 months of treatment. One patient had a recurrence in the upper eyelid 6 months after an initial PR; he then received 30 Gy of external-beam radiotherapy (EBRT). His disease later progressed again in the orbit and he is currently being considered for other treatments. A second patient who attained a PR has remained stable with no progression 12 months after treatment. With a median follow-up time of 20 months (range 6-44 months), there were no cases of distant (extraorbital) relapse. All 12 patients experienced grade I or II transient pancytopenia during the first 3 months after enrollment in the trial. There were no episodes of grade III or IV myelosuppression. The estimated absorbed radiation dose to the orbital soft tissues was <3 Gy, 10 times lower than that with EBRT. CONCLUSIONS: Rituximab followed by (90)Y ibritumomab tiuxetan is an effective and safe front-line treatment for early-stage extranodal indolent B-cell lymphoma of the ocular adnexa.

The addition of rituximab to CHOP chemotherapy improves overall and failure-free survival for follicular grade 3 lymphoma.

BACKGROUND: The benefit of adding rituximab to anthracycline-based therapy for follicular lymphoma grade 3 has not been studied. PATIENTS AND METHODS: We retrospectively reviewed the records of 45 patients with follicular grade 3 lymphoma who were treated with rituximab and the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) at The University of Texas MD Anderson Cancer Center. Response rate, failure-free survival (FFS), and overall survival (OS) were estimated and a historical comparison to CHOP-only-treated patients was made. RESULTS: The International Prognostic Index (IPI) distribution was 47% low, 36% low intermediate, 13% high intermediate, and 4% high risk. The complete response rate was 96%. Forty-four of 45 patients are still alive. Median follow-up for the alive patients is 3.5 years. The 3-year FFS rate according to the IPI was 80% [95% confidence interval (CI) 64% to 100%] in low, 81% in low intermediate (95% CI 64% to 100%), and 50% (95% CI 25% to 100%) in high-intermediate/high-risk patient group. The addition of rituximab to CHOP improved both 5-year FFS, 71% (95% CI 58% to 87%) compared with 44% (95% CI 36% to 55%) with P value of 0.019, and 5-year OS, 98% (95% CI 93% to 100%) compared with 75% (95% CI 67% to 84%) with P value of 0.0034. CONCLUSION: The addition of rituximab to CHOP provided a high response rate and excellent early survival. Poor-risk patients continue to demonstrate a high rate of failure despite the use of rituximab.

Seroprevalence of HPV 6, 11, 16 and 18 and correlates of exposure in unvaccinated women aged 16-64 years in Puerto Rico.

BACKGROUND: To understand risk factors for HPV exposure in Puerto Rican women, we evaluated HPV 6, 11, 16, and 18 serology in women aged living in the San Juan metropolitan area. METHODS: As part of a cross-sectional study, a population-based sample of 524 HPV unvaccinated Hispanic women ages 16-64 years completed face-to-face and computer assisted interviews and provided blood and self-collected anal and cervical specimens. Serology used multiplex virus-like particle based-IgG ELISA and HPV DNA was detected with L1-consensus PCR. RESULTS: 32% and 47% were seropositive to HPV types included in the bivalent (16/18) and quadrivalent (6/11/16/18) vaccines, respectively. Type-specific seroprevalence was HPV6 - 29%, HPV11 - 18%, HPV16 - 23%, and HPV18 - 17%; seroprevalence was high in the youngest age-group (16-19: 26-37%). HPV seropositivity was associated with having ≥ 3 lifetime sexual partners (OR=2.5, 95% CI=1.7-3.9) and detection of anogenital HPV DNA (OR=1.8, 95% CI=1.2-2.6). CONCLUSIONS: The high cumulative exposure of HPV vaccine types 6/11/16/18 in this Hispanic population was influenced by factors related to HPV exposure through sexual behavior. High seroprevalence in the youngest age-group indicates early age of exposure to HPV in Puerto Rico, highlighting the need for HPV vaccination starting prior to age 16.

Factors Associated with HPV Vaccine Awareness in a Population-Based Sample of Hispanic Women in Puerto Rico.

OBJECTIVES: The objective of this study was to investigate the factors associated with HPV awareness among women aged 16 to 64 years, among underserved minority Hispanic women living in Puerto Rico. METHODS: A population-based, cross-sectional sample of 566 women, ages 16 to 64 years, living in the San Juan metropolitan area were surveyed regarding sexual behavior, HPV knowledge, and HPV vaccine uptake. Data was analyzed using descriptive statistics and multivariate logistic regression. RESULTS: Overall, 64.8 % of the women in the sample had heard about the HPV vaccine. Among those in the recommended catch-up vaccination age range (16-26 years, n = 86), 4.7 % had received at least one dose of the HPV vaccine. Of those aware of the availability of the HPV vaccine, most had learned about it through the media, whereas, only 39.6 % had learned about it from a physician. Multivariate logistic regression analysis showed that HPV awareness (OR 8.6; 95 % CI 5.0-14.8) and having had an abnormal Pap smear (OR 2.0; 95 % CI 1.2-3.4) were associated with HPV vaccine awareness (p < 0.05). CONCLUSION: HPV vaccine awareness among Hispanic women in the San Juan metropolitan area of Puerto Rico continues to be low. Strong recommendations from physicians and participation in HPV vaccine educational efforts are essential if the rate of HPV vaccination is to increase in the targeted population. Compared to the USA, and to their US Hispanic counterparts, a health disparity with regard to HPV vaccine awareness and coverage is evident in Puerto Rico; targeted action to deal with this disparity is urgently needed.

Prevalence, genotyping, and correlates of anogenital HPV infection in a population-based sample of women in Puerto Rico.

BACKGROUND: Oncogenic HPV infection is associated to anogenital cancer. We estimate the prevalence and correlates of anogenital HPV infection among a population-based sample of women aged 16-64 years living in the metropolitan area of Puerto Rico. METHODS: 564 women completed face-to-face and computer assisted interviews and self-collected anal and cervical specimens. HPV DNA testing used MY09/MY11 consensus HPV L1 primers and beta-globin as an internal control for sample amplification. Positive specimens were typed by dot-blot hybridization. RESULTS: Weighted prevalence of cervical, anal, and cervical/anal co-infection was 29.4%, 38.6%, and 17.1%, respectively. The commonest oncogenic HPV types detected in the cervix and anus were: 68 (8% vs. 7%) and 16 (5.5% vs. 5.1%), correspondingly. Having ≥3 lifetime sexual partners (OR: 2.3; 95% CI: 1.5-3.5) and last year anal intercourse (OR: 1.6; 95% CI: 1.1-2.5) increased the odds of anogenital HPV infection. Cervical infection was independently associated to anal infection (OR: 3.0; 95% CI: 2.0-4.6). CONCLUSIONS: Similar to others, our results confirm the burden of anogenital HPV infection in women and its relationship with sexual behavior. As vaccination increases, future studies should monitor changing trends in HPV infection in this population, and the relationship between anal and cervical HPV-related disease.

Multivariate analysis of prognostic factors in stage IV follicular low-grade lymphoma: a risk model.

We analyzed the records of 96 previously untreated patients with stage IV follicular low-grade lymphoma (FLGL) uniformly treated with cyclophosphamide, doxorubicin, vincristine, prednisone, and bleomycin (CHOP-Bleo) chemotherapy from 1972 to 1982. The overall complete remission (CR) rate was 77%. At a median follow-up of 138 months, the 10-year cause-specific survival rate was 42% with a median survival of 100 months. Failure-free survival (FFS) was 15% at 10 years with a median FFS of 30 months. Multivariate analysis showed peripheral lymph node size (LN), degree of marrow involvement, and sex, in that order, to be important for FFS, while the number of extranodal sites (#ENS), LN, sex, and degree of marrow involvement were important for cause-specific survival. We devised a tumor burden (TB) model, incorporating #ENS, LN, and degree of marrow involvement. Three groups were identified with statistically significant differences in cause-specific survival and FFS. Those with low TB (one ENS exclusive of extensive marrow and nodal disease less than 5 cm) had a 10-year cause-specific survival of 73% compared with 24% for patients with high TB (greater than or equal to two ENS and nodal disease greater than or equal to 5 cm) (P less than .001) and 40% for those with intermediate TB (either greater than or equal to 2 ENS, or extensive marrow only, or nodal disease greater than 5 cm) (P = .050). Patients with low TB had a 10-year FFS rate of 32%, while the intermediate and high TB groups had 10% and 9% FFS, respectively (P = .003). Because sex was a very strong prognostic variable, we created a risk model for survival and FFS based on TB and sex. Females with low TB had the best prognosis (92% survival and 50% FFS at 10 years) and males with high TB had the worst outlook (median survival and FFS, 43 and 12 months, respectively). Other TB-sex combinations defined two groups with statistically significant differences in survival but comparable FFS. This model should aid in the design and analysis of future trials.

Phase I study of the combination of fludarabine, mitoxantrone, and dexamethasone in low-grade lymphoma.

PURPOSE: Fludarabine is an active agent for patients with low-grade lymphoma (LGL) but has mainly been used as a single agent. This trial was designed to define the maximum-tolerated dose (MTD) of a combination of fludarabine, mitoxantrone, and dexamethasone (FND), to identify the toxicities of these agents in combination, and to make preliminary observations about the efficacy of this combination. PATIENTS AND METHODS: Twenty-one patients with recurrent LGL or follicular large-cell lymphoma were treated, in cohorts of three, at stepwise escalating doses. Patients were required to have adequate marrow function and normal renal, hepatic, and cardiac function. RESULTS: The MTD of the combination was found to be as follows: fludarabine, 25 mg/m2/d (days 1 to 3); mitoxantrone, 10 mg/m2 (day 1); and dexamethasone, 20 mg/d (days 1 to 5). Each course was administered monthly, and up to eight courses were given. Dose-limiting toxicities were neutropenia and infections. Thrombocytopenia was modest. Nonhematologic toxicity was very modest. Responses were seen at every dose level. The overall response rate was 71%, with a 43% complete remission (CR) rate. The median duration of CR was 18 months (with follow-up duration from 13 to 28+ months). CONCLUSION: FND was well tolerated in this population. While our primary aim was to define the MTD, our preliminary observations on the efficacy of the regimen were favorable. The overall response rate was high, there was a high fraction of CRs, and our early impression is that these responses are durable.

Primary cutaneous non-Hodgkin's lymphoma of Ann Arbor stage I: preferential cutaneous relapses but high cure rate with doxorubicin-based therapy.

PURPOSE: Establish frequency, presenting features, response and relapse patterns, and outcome of primary cutaneous non-Hodgkin's lymphoma (PCNHL). PATIENTS AND METHODS: Review of untreated patients, older than 16 years, presenting between 1971 and 1993 with cutaneous lymphoma, not mycosis fungoides, and Ann Arbor stage I. RESULTS: We identified 46 patients, 27 males, with median age of 57 years. Treatment was radiotherapy in 10 patients, doxorubicin-based therapy in 33 patients that was followed by radiotherapy in 25 patients, and other combination with radiotherapy in one patient. The complete response rate was 95%. After a median follow-up of 140 months (range, 61 to 284 months), 18 patients have relapsed, and 14 have died from lymphoma. The first failure was exclusively cutaneous in 50% of relapses. For the 44 treated patients, progression-free survival (PFS; actuarial +/- SE) was 61% +/- 7% and survival was 58% +/- 9% at 12 years. For the 18 patients with diffuse large B-cell lymphoma, after doxorubicin-based regimens, PFS was 71% +/- 12% (P = .0003) versus 0% after radiotherapy; survival was 77% +/- 12% versus 25% +/- 22% (P = 004), respectively. For the nine patients with follicular center-cell lymphoma treated with combined modality, the 12-year PFS was 89% +/- 11% and survival 70% +/- 18%. CONCLUSION: PCNHL is rare, and its first relapse is exclusively cutaneous in 50% of patients. Patients with diffuse large B-cell lymphoma are curable with doxorubicin-based regimens but not with radiotherapy. Prospective studies in PCNHL should define the cytogenetics, the basis for cutaneous tropism, the prognosis of histologic subtypes, and the role of radiotherapy.

Trimetrexate in relapsed T-cell lymphoma with skin involvement.

PURPOSE: Methotrexate (MTX) is active against lymphomas, but transport or polyglutamylation mutations confer MTX resistance. Because trimetrexate (TMTX) enters cells by passive diffusion and is not polyglutamylated, its activity in relapsed T-cell lymphoma was investigated. PATIENTS AND METHODS: Eligible patients had histologically confirmed relapsed T-cell lymphoma involving the skin, had received more than one previous regimen, were older than 16 years, had normal organ function, and had no CNS disease or serious infections, including human immunodeficiency virus. TMTX (200 mg/m(2)) was given intravenously every 14 days without topical or systemic corticosteroids. Patients who responded received up to 12 doses. RESULTS: Twenty patients were assessable for response. Median age was 59 years (range, 45 to 87 years); 13 patients were men. Three patients had anaplastic large-cell lymphoma, 15 had mycosis fungoides or Sézary syndrome (14 with large-cell transformation), and two had peripheral T-cell lymphoma. Serum lactate dehydrogenase was high in 35%, and beta-2 microglobulin was more than 3.0 mg/L in 35% of patients. The median number of previous regimens was three (range, two to 15) and included MTX in five patients. Disease was refractory to the regimen immediately preceding TMTX in 85% of patients. Responses were complete in one and partial in eight patients (overall response rate, 45%). Two of five patients previously treated with MTX responded. Grade 3 or 4 mucositis was observed after 4%, infection after 3%, neutropenic fever after 6%, neutrophils less than 100/microL after 4%, and platelets less than 10,000/microL after 3% of TMTX doses. CONCLUSION: TMTX is active with acceptable toxicity in this population and merits further investigation.

ESHAP--an effective chemotherapy regimen in refractory and relapsing lymphoma: a 4-year follow-up study.

PURPOSE: This study attempted to determine the efficacy of the combination of etoposide (VP-16), methyl-prednisolone, and cytarabine (Ara-C) with or without cisplatin in relapsing and refractory adult lymphoma patients. PATIENTS AND METHODS: The first 63 patients were randomized to receive VP-16 40 mg/m2/d for 4 days, methylprednisolone 500 mg intravenously daily for 5 days, and Ara-C 2 g/m2 intravenously over 2 to 3 hours on day 5 with or without cisplatin 25 mg/m2 IV administered by 24-hour infusion for 4 days (ESHA +/- P). Markedly different responses between ESHA (33%) and ESHAP (75%) led to deletion of the ESHA arm. A total of 122 patients on the ESHAP regimen were studied. RESULTS: Forty-five patients (37%) attained a complete remission (CR) and 33 (27%) attained a partial remission (PR), for a total response rate of 64%. The median duration of CR was 20 months, with 28% of remitters still in CR at 3 years. The overall median survival duration was 14 months; the survival rate at 3 years was 31%. Overall time to treatment failure (TTF) showed 10% of all patients to be alive and disease-free at 40 months. Response and survival rates were similar in patients with low-grade (n = 34), intermediate-grade (n = 67), transformed (n = 18), and high-grade (n = 3) lymphoma. The most significant factors for response and survival by multivariate analysis were the serum lactic dehydrogenase (LDH) level, tumor burden, and age (when analyzed as a continuous variable), while prior CR was highly significant by univariate analysis. A significant difference in survival was noted for patients with normal LDH levels and low- or intermediate-tumor burden or patients with low tumor burden and elevated LDH levels (55% 3-year survival rate) versus patients with elevated LDH levels and intermediate or high tumor burden (< 20%). Major toxicities included myelosuppression, with a median granulocyte count of 500/microL and platelet count of 70,000/microL. CONCLUSION: ESHAP was found to be an active, tolerable chemotherapy regimen for relapsing and refractory lymphoma. Applying a prognostic model based on tumor burden and serum LDH level shows significant differences in survival in this patient population.

Results of a salvage treatment program for relapsing lymphoma: MINE consolidated with ESHAP.

PURPOSE: We report the results of a prospective trial in which patients with relapsing non-Hodgkin's lymphomas were sequentially treated with two regimens (mesna, ifosfamide, mitoxantrone, and etoposide [MINE], and etoposide, methylprednisolone, cytarabine, and cisplatin [ESHAP]) if they had no history of disease resistance to these drugs. PATIENTS AND METHODS: Ninety-two patients received MINE (mesna 4 g/m2, ifosfamide 4 g/m2, mitoxantrone 8 mg/m2, and etoposide 195 mg/m2) for a maximum of six courses followed by ESHAP (etoposide 240 mg/m2, methylprednisone 500 mg/d, high-dose cytarabine 2 g/m2, and cisplatin 100 mg/m2) for three courses to consolidate complete response (CR) or for a maximum of six cycles after a partial response (PR) or no response to MINE. Pretreatment serum levels of lactate dehydrogenase (LDH) and beta 2-microglobulin (beta 2M) were documented in 80 of 92 patients. RESULTS: The response rate to MINE-ESHAP was 69% (48% CRs and 21% PRs), with a median survival time of 24 months and median time to treatment failure of 12 months. The median time to treatment failure according to histology was as follows: low-grade histologies, 16 months; low-grade transformed to intermediate-grade, 8 months; and intermediate-grade, 5 months. The most serious complication was myelosuppression, which resulted in two deaths due to neutropenic sepsis. A risk factor model based on beta 2M and LDH levels before salvage treatment showed three categories of risk, with 36-month survival rates as follows: low (beta 2M < 3 mg/dL and LDH normal), 61%; intermediate (beta 2M > or = 3 mg/dL or LDH above normal), 23%; and high (beta 2M > or = 3 mg/dL and LDH above normal), 0%. CONCLUSION: MINE-ESHAP is an effective salvage strategy for patients with recurrent lymphoma. Toxicity was acceptable. Factors that determine prognostic categories at relapse merit further study.

No effect of 96-hour paclitaxel infusion in patients with relapsed non-Hodgkin's lymphoma refractory to a 3-hour infusion schedule.

PURPOSE: Preclinical data suggest that the efficacy of paclitaxel (Taxol; Bristol-Myers Squibb Co, Princeton, NJ) is schedule-dependent. Schedule dependency is currently under investigation in ongoing randomized trials. PATIENTS AND METHODS: Twelve patients with relapsed non-Hodgkin's lymphoma (NHL) refractory to a 3-hour infusion of 200 mg/m2 Taxol were crossed over to receive a 96-hour infusion of 140 mg/m2 Taxol every 3 weeks in an outpatient setting. Premedication with corticosteroids and antihistamines was not used. Patients who did not achieve at least a partial remission (PR) after two courses or whose disease progressed after one course were removed from the study. RESULTS: All 12 patients were assessable for response. Eleven patients received at least two courses and one patient received one course of 96-hour Taxol infusion. None of the 12 patients crossed over to receive 96-hour Taxol infusion achieved a PR or complete response (CR). Eight patients (67%) developed progressive lymphoma, three (25%) had stable disease, and only one (8%) had a minor response. No major hypersensitivity reactions or life-threatening toxicities were observed. CONCLUSION: Ninety-six-hour Taxol infusion does not produce significant responses in patients with NHL refractory to 3-hour Taxol infusion. Until the results of an ongoing multicenter trial comparing a 3- with a 96-hour infusion are published, the use of 96-hour Taxol infusion in NHL patients should be restricted to investigational programs. Because 48- to 72-hour infusions can produce higher plasma concentrations of Taxol than a 96-hour infusion, these schedules should be investigated to determine if they can induce better clinical responses.

Fludarabine, mitoxantrone, and dexamethasone: an effective new regimen for indolent lymphoma.

PURPOSE: Although most patients with indolent lymphomas respond to initial therapy, virtually all experience relapse. Secondary therapy is often beneficial, but responses are rarely, if ever, durable. We conducted this phase II trail to evaluate the therapeutic efficacy and toxicity of fludarabine, mitoxantrone, and dexamethasone (FND) in patients with relapsed indolent lymphoma. PATIENTS AND METHODS: Fifty-one patients with recurrent or refractory indolent lymphoma were treated with a regimen of fludarabine 25 mg/m2/d intravenously (IV) on days 1 to 3, mitoxantrone 10 mg/m2 IV on day 1, and dexamethasone 20 mg/d IV or orally on days 1 to 5. Treatment was repeated at 4-week intervals for a maximum of eight courses. Late in the course of this trial, trimethoprim-sulfamethoxazole (TMP-SMX) was incorporated for Pneumocystis carinii (PCP) prophylaxis. RESULTS: Responses were complete (CR) in 24 patients (47%) and partial (PR) in 24 (47%). The median failure-free survival time was 21 months for CR patients and 9 months for PR patients. Notable activity of FND was seen even in the elderly, in those with high serum lactate dehydrogenase (LDH) or beta2-microglobulin levels, and in those with multiple prior treatment regimens. The predominant toxic effects were myelosuppression and infections; other toxic effects were modest. Infections occurred in 12% of courses. Almost half of the infections were proven or suspected opportunistic infections, including six cases of dermatomal herpes zoster and two cases of proven PCP pneumonia. CONCLUSION: The FND combination is highly active in patients with recurrent or relapsed indolent lymphoma and results in a high percentage of CRs. Because of the risk of opportunistic infections, we currently recommend prophylaxis with TMP-SMX and advise deletion of corticosteroids for patients who develop opportunistic infections.