An international phase II trial of single-agent lenalidomide for relapsed or refractory aggressive B-cell non-Hodgkin’s lymphoma

BackgroundLenalidomide is an immunomodulatory agent with antitumor activity in B-cell malignancies. This phase II trial aimed to demonstrate the safety and efficacy of lenalidomide in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular grade 3 lymphoma (FL-III), or transformed lymphoma (TL).MethodsPatients received oral lenalidomide 25 mg on days 1–21 every 28 days as tolerated or until progression. The primary end point was overall response rate (ORR).ResultsTwo hundred and seventeen patients enrolled and received lenalidomide. The ORR was 35% (77/217), with 13% (29/217) complete remission (CR), 22% (48/217) partial remission, and 21% (45/217) with stable disease. The ORR for DLBCL was 28% (30/108), 42% (24/57) for MCL, 42% (8/19) for FL-III, and 45% (15/33) for TL. Median progression-free survival for all 217 patients was 3.7 months [95% confidence interval (CI) 2.7–5.1]. For 77 responders, the median response duration lasted 10.6 months (95% CI 7.0–NR). Median response duration was not reached in 29 patients who achieved a CR and in responding patients with FL-III or MCL. The most common adverse event was myelosuppression with grade 4 neutropenia and thrombocytopenia in 17% and 6%, respectively.ConclusionLenalidomide is well tolerated and produces durable responses in patients with relapsed or refractory aggressive non-Hodgkin’s lymphoma.     

Advances in the management of patients with non-Hodgkin’s lymphoma

Non-Hodgkin’s lymphoma is the fifth most common cause of death due to cancer and has been rising at a rate of 4% per year for the last four decades. Although ‘traditional’ chemotherapy and radiotherapy have had important contributions to improving outcomes, new tools in the treatment of non-Hodgkin’s lymphoma are needed. This review describes therapeutic modalities that are currently being used or are in the process of being developed and which are based on concepts divergent from ‘traditional’ approaches to managing non-Hodgkin’s lymphoma.     

Preliminary outcome of rituximab-containing salvage regimens on relapsed or refractory B-cell non-Hodgkin’s lymphoma: single institution experience

Relapsed or refractory aggressive non-Hodgkin’s lym- phoma (NHL) is known to have a poor prognosis. The over- all response rates of second line salvage regimens such as EPOCH (CTX, VCR, ADM, prednisone and VP16), DICE (dexamethasone, DDP and VP16), DHAP (dexametha- sone, Ara-c and DDP) and ESHAP (VP16, dexamethasone, Ara-c and DDP) range from 30% to 70% with complete remission rates (CR) from 19.2% to 35.0%[1–5]. Although high dose chemotherapy supported by autologous hae…     

Use of bortezomib in B-cell non-Hodgkin’s lymphoma

The ubiquitin–proteasome pathway plays a critical role in the regulated degradation of proteins involved in cell cycle control and tumor growth. Bortezomib (Velcade^®, formerly known as PS-341) is a potent proteasome inhibitor. In preclinical studies, bortezomib has demonstrated activity against a variety of B-cell malignancies by inducing apoptosis and sensitizing tumor cells to radiation or chemotherapy. Based on these findings, clinical trials have been conducted with bortezomib in B-cell non-Hodgkin’s lymphoma. In these studies, bortezomib was generally well tolerated with manageable toxicities and showed promising clinical activity. Mantle cell lymphoma was significantly more sensitive to bortezomib than other non-Hodgkin’s lymphomas. Bortezomib may have far-reaching potential in the treatment of B-cell non-Hodgkin’s lymphoma.     

Primary non-Hodgkin’s lymphoma of the bone

Primary non-Hodgkin’s lymphoma of the bone is an unusual entity. Twenty-five patients with diffuse large cell lymphoma of the bone were registered at the Tata Memorial Hospital (TMH) from August, 1991, to May, 2002. Pain at the local site and soft tissue swelling were the commonest symptoms. Involvement of the bones in the lower half of the body was more frequent than the bones in the upper half. Osteolytic lesions and an associated soft tissue mass were the common radiological findings. Nineteen patients received CHOP chemotherapy and five received COP chemotherapy. Twenty-three patients received involved field radiotherapy. The overall response to therapy was 96%. On follow-up, two patients had a nodal relapse. One patient died of progressive disease, and one patient died of cryptococcal meningitis. There were no deaths due to treatment-related toxicity. The mean progression free survival was 9.39 yr and the overall survival was 11.66 yr. The median overall survival has not been reached. At last follow-up, 21 patients were being following up at TMH and are free of disease. Conclusion: Primary bone lymphoma is a malignancy that is highly curable with a combination of chemotherapy and radiotherapy.     

Addition of rituximab to chop does not increase the risk of cardiotoxicity in patients with non-Hodgkin’s lymphoma

Background The addition of rituximab to doxorubicin-containing standard chemotherapy significantly improves response to therapy and reduces the risk of death in B-cell non-Hodgkin’s lymphoma (NHL) patients. However, the impact of this approach on doxorubicin-induced cardiotoxicity has not been elucidated. Methods Patients who had been planned to receive CHOP or rituximab plus CHOP (R-CHOP) combination chemotherapy with a diagnosis of NHL were included in the study. In all patients, systolic and diastolic parameters were measured by using conventional and pulsed-wave tissue Doppler echocardiography, which is more sensitive than conventional lead-dependent techniques, both before and in the sixth month of therapy. Results There were 28 (M/F; 14/14) patients on CHOP and 33 (M/F; 16/17) patients on R-CHOP. Median age in CHOP and R-CHOP was 49 and 50 years (P = 0.44), respectively. Cumulative doxorubicin doses were 280 and 286 mg/m² on CHOP and R-CHOP (P = 0.65), respectively. None of the patients developed clinically evident congestive heart failure. Parameters of systolic function such as LVEF and FS did not significantly change in any patients. In both arms, tissue Doppler parameters of diastolic function such as lateral E and septal E velocity of mitral annulus decreased significantly after therapy (P < 0.001). However, the decrease in diastolic function was similar in both arms (P > 0.05). Conventional Doppler echocardiography yielded consistent findings. Conclusion Both CHOP and R-CHOP cause diastolic dysfunction in the early period following their administration. The addition of rituximab to CHOP chemotherapy does not significantly increase the risk of doxorubicin-induced cardiotoxicity during this period.     

Immunotoxin – a new treatment option in patients with relapsed and refractory Hodgkin lymphoma

Background

Even though Hodgkin lymphoma is a highly curable disease, some of the patients have either a refractory disease or experience a relapse following a successful primary therapy. Durable responses and remissions in patients with relapsed or refractory disease may be achieved in approximately one-half with salvage chemotherapy followed by high dose chemotherapy (HDT) and autologous hematopoietic cell rescue (SCT). On the other hand, patients who relapse after HDT and autologous SCT or those who have failed at least two prior multi-agent chemotherapy regimens and are not candidates for HDT have limited treatment options.

Conclusions

A new treatment option in this population is an immunotoxin Brentuximab vedotin composed of a CD30 directed antibody linked to the antitubulin agent monomethyl auristatin E. It has demonstrated a substantial effectiveness and an acceptable toxicity. In the pivotal study, the overall response rate was 75% with 34% of complete remissions. The median durations of response were 20.5 and 6.7 months for those with complete remission and all responding patients, respectively. The median overall survival was 40.5 months (3-years overall survival 54%) and the median progression-free survival 9.3 months. The most common non-hematologic toxicities were peripheral sensory neuropathy, nausea, and fatigue while the most common severe side effects were neutropenia, thrombocytopenia, anemia, and peripheral sensory neuropathy.     

Bendamustine therapy in patients with relapsed or refractory Waldenström's macroglobulinemia

We report the treatment outcome for 30 relapsed/refractory Waldenström's macroglobulinemia (WM) patients following bendamustine-containing therapy. Treatment consisted of bendamustine (90 mg/m² I.V. on days 1, 2) and rituximab (375 mg/m² I.V. on either day 1 or 2) for 24 patients. Six rituximab-intolerant patients received bendamustine alone (n = 4) or with ofatumumab (1000 mg I.V. on day 1; n = 2). Each cycle was 4 weeks, and median number of treatment cycles was 5. At best response, median serum IgM declined from 3980 to 698 mg/dL (P < .0001), and hematocrit rose from 31.9% to 36.6% (P = .0002). Overall response rate was 83.3%, with 5 VGPR and 20 PR. The median estimated progression-free survival for all patients was 13.2 months. Overall therapy was well tolerated. Prolonged myelosuppression was more common in patients who received prior nucleoside analogues. Bendamustine is active and produces durable responses in previously treated WM, both as monotherapy and with CD20-directed monoclonal antibodies.     

A multicenter phase II trial of etoposide, methylprednisolone, high-dose cytarabine, and oxaliplatin for patients with primary refractory/relapsed aggressive non-Hodgkin’s lymphoma

Purpose  We investigated the efficacy and toxicity of the etoposide, methylprednisolone, high-dose cytarabine, and oxaliplatin (ESHAOx), in which oxaliplatin (Ox) was substituted for cisplatin in the ESHAP [etoposide (E), methylprednisolone (S), high-dose cytarabine (HA), and cisplatin (P)] regimen, for patients with refractory/relapsed aggressive non-Hodgkin’s lymphoma (NHL). Materials and methods  The ESHAOx consisted of E (40 mg/m² on days 1–4), S (500 mg on days 1–5), HA (2 g/m² on day 5), and Ox (130 mg/m² on day 1) every 3 weeks to a maximum of six cycles. Responses were assessed every three cycles. Results  Twenty-seven patients were enrolled (19 with relapsed and 8 with refractory; 10 with an IPI score of 3–5). The overall response rate was 63% [95% confidence interval (95% CI) 45–81%], including eight complete remissions (CR) and one unconfirmed CR (33%). The median duration of response was 9.9 months (95% CI 5.7–14.2 months). After a median follow-up of 18.6 months, the median progression-free and overall survival was 5.3 months (95% CI 3.9–6.7 months) and 15.1 months (95% CI 9.4–20.9 months), respectively, with a 1-year survival rate of 61.5%. Most common grade 3/4 hematologic toxicities were neutropenia (56%) and thrombocytopenia (35%), whereas no patient experienced grade 3/4 renal or neurotoxicity. Conclusion  The efficacy and toxicity profiles suggested that the ESHAOx can be an alternative option for patients with refractory/relapsed aggressive NHL. S. J. Sym and D. H. Lee contributed equally to this study.     

Salvage chemotherapy with alternating MINE–ESHAP regimen in relapsed or refractory Hodgkin’s lymphoma followed by autologous stem-cell transplantation

BackgroundHigh-dose chemotherapy (HDT) followed by autologous stem-cell transplantation (ASCT) is considered the gold standard in the treatment of patients with relapsed or refractory Hodgkin’s lymphoma (HL). However, the optimal salvage regimen has not yet been established.Patients and methodsWe retrospectively analyzed the efficacy and toxicity of MINE (mesna, ifosfamide, mitoxantrone, and etoposide) alternated with ESHAP (etoposide, methylprednisolone, high-dose cytarabine, and cisplatin) in the treatment of 61 relapsed or refractory HL patients after ABVD-based chemotherapy.ResultsOverall, 25 patients (41%) achieved a complete response (CR), 23 (38%) a partial response (PR), 4 (7%) a stable disease, and 8 (13%) progressed for an overall response rate of 79%. Response to first-line chemotherapy was the most important prognostic factor for response to MINE–ESHAP (P = 0.041). No grade 4 extrahematologic toxic effects or toxic deaths were observed. Adequate peripheral blood stem-cell collection was achieved in 56 of 59 (95%) mobilized patients. Overall survival and event-free survival after HDT and ASCT were significantly higher for patients achieving CR/PR in comparison with those refractory to MINE–ESHAP (46% and 35% versus 74% and 69%, respectively).ConclusionMINE–ESHAP results in a high response rate with acceptable toxicity in patients with HL having failed ABVD-based treatment.     

Isolated renal relapse of a case with non-Hodgkin’s lymphoma

A 29-year-old woman with left pleural effusion and a mass in anterior mediastinum was admitted. Transthoracic needle aspiration from the mass revealed findings consistent with nodular sclerosis variety of Hodgkin’s disease. The patient was in remission after six cycles of ABVD followed by mediastinal radiotherapy. Ten months later CT scan showed three hypodense masses in the right kidney. Ultrasound guided renal biopsy revealed diffuse large B cell lymphoma. Retrospective re-evaluation of the archival specimens of the mediastinal mass was also consistent with diffuse large B cell lymphoma. After induction chemotherapy (four cycles of DHAP) she underwent high dose chemotherapy (BEAM) and autologous peripheral blood stem cell transplantation. She is still in remission for 7 years after transplantation. In conclusion, renal involvement during advanced lymphoma is quite common but isolated renal relapse in NHL is a rare situation. Although renal infiltration generally shows a poor prognosis, long-term survival may be achieved with high dose chemotherapy and autologous peripheral blood stem cell transplantation.     

Plasma kinetics of a cholesterol-rich microemulsion (LDE) in patients with Hodgkin’s and non-Hodgkin’s lymphoma and a preliminary study on the toxicity of etoposide associated with LDE

Background: Neoplastic diseases are often associated with low plasma low-density lipoprotein (LDL) cholesterol and diminished LDL clearance due to upregulation in cancer cells of the receptors that internalize the lipoprotein. Thus, it is possible to use LDL or cholesterol-rich microemulsions (LDE) that bind to LDL receptors as carriers of antineoplastic agents to concentrate those drugs into cancer tissues. Our aim was to determine whether LDL cholesterol concentration plus LDE increased clearance occur in lymphomas. Patients and methods: The LDE labeled with [³ H]-cholesteryl oleate was injected into four Hodgkin’s and 12 non-Hodgkin’s lymphoma patients and into 16 healthy control subjects and the LDE plasma residence time (RT) was determined from sequential plasma samples. Two volunteers with relapsed/refractory lymphoma were treated with 300 mg/m² body surface etoposide associated with LDE in six cycles at 3-week intervals. Results: The LDL cholesterol was lower in lymphoma patients than in controls (94±52 and 115±16 mg/dL, p=0.0362, respectively). The LDE RT was 49% smaller in lymphoma patients than in controls (RT=21.9 and 45.7 h; p=0.0134), with positive correlation between RT and LDL cholesterol. LDE-etoposide showed no considerable toxicity in all cycles in the two treated patients and the disease remained stable during the treatment. Conclusions: Our results suggest that lymphomas overexpress LDL receptors that make room for using LDE as drug-targeting vehicle and that the LDE-etoposide preparation is suitable for patient use.     

IL-10 induces the development of immunosuppressive CD14+HLA-DRlow/? monocytes in B-cell non-Hodgkin lymphoma

The biological role of monocytes and macrophages in B-cell non-Hodgkin lymphoma (NHL) is not fully understood. We have previously reported that monocytes from patients with B-cell NHL have an immunosuppressive CD14⁺HLA-DR^low/− phenotype that correlates with a poor prognosis. However, the underlying mechanism by which CD14⁺HLA-DR^low/− monocytes develop in lymphoma is unknown. In the present study, we found that interleukin (IL)-10, which is increased in the serum of patients with B-cell NHL, induced the development of the CD4⁺HLA-DR^low/− population. Using peripheral blood samples from patients with B-cell NHL, we found that absolute numbers of CD14⁺ monocytic cells with an HLA-DR^low/− phenotype were higher than healthy controls and correlated with a higher International Prognostic Index score. IL-10 serum levels were elevated in lymphoma patients compared with controls and were associated with increased peripheral monocyte counts. Treatment of monocytes with IL-10 in vitro significantly decreased HLA-DR expression and resulted in the expansion of CD14⁺HLA-DR^low/− population. We found that lymphoma B cells produce IL-10 and supernatants from cultured lymphoma cells increased the CD14⁺HLA-DR^low/− population. Furthermore, we found that IL-10-induced CD14⁺HLA-DR^low/− monocytes inhibited the activation and proliferation of T cells. Taken together, these results suggest that elevated IL-10 serum levels contribute to increased numbers of immunosuppressive CD14⁺HLA-DR^low/− monocytes in B-cell NHL.     

Reactivation of hepatitis B virus infection with cytotoxic therapy in non-Hodgkin’s lymphoma

In patients with non-Hodgkin's lymphoma (NHL), there are some well-known tumor-related adverse prognostic factors that may increase the mortality rate. However, secondary factors such as viral hepatitis carriers that may decrease the cure rates are usually ignored. Reactivation of hepatitis B virus (HBV) infection in patients undergoing cytotoxic treatment for NHL is a well-known complication. Charts of 112 patients with NHL were retrospectively analyzed regarding their hepatitis serology, the indirect effects of seropositivity on disease outcome, and the precautions undertaken in these seropositive patients with NHL. Twelve patients (11%) with HBsAg positivity and two patients (1.7%) with antibody to hepatitis C virus positivity were detected. Eight out of 12 patients (67%) with HBsAg positivity and two patients (50%) with anti-HCV positivity showed reactivation of hepatitis during treatment of NHL. No reactivation was detected in four patients seropositive for HBV, who were given lamivudine prophylaxis before the initiation of chemotherapy schedules. Among patients with hepatitis reactivation, two were treated with lamivudine resulting in dramatic improvement and clinical remission of the disease. The remaining six patients with reactivation were left untreated, resulting in four deaths (67%) due to liver failure secondary to HBV and two deaths secondary to delayed treatment of NHL. One patient seropositive for anti-HCV also developed chronic hepatitis C. Determination of hepatitis serology in all patients with NHL before any chemotherapy administration is crucial, but insufficient, if not taken into consideration. In seropositive patients, HBV DNA should be determined and antiviral prophylaxis with lamivudine should be initiated before any treatment.     

Prevention and treatment of hyperuricemia with rasburicase in children with leukemia and non-Hodgkin’s lymphoma

To prevent acute renal failure in children at risk for developing tumor lysis syndrome due to acute lymphoblastic leukemia or non-Hodgkin’s lymphoma treated according to international BFM protocols, we investigated recombinant urate oxidase (rasburicase) in the first Central European openlabeled, prospective, multicenter phase IV trial. Rasburicase was administered intravenously, at 0.2 mg/kg for 5 consecutive days to 36 patients. Blood levels of uric acid, creatinine, phosphorus, calcium, lactate dehydrogenase and complete blood count were measured daily during rasburicase treatment and on days 6, 7 and 12. Initial uric acid level decreased significantly by 4 hours (from 343 μmol/L to 58 μmol/L, p<0.001), except for one steroid-resistant patient who required hemodialysis on day 14 after having introduced combined cytostatic treatment. Comparing the data of a subgroup of 12 patients receiving rasburicase with that of a historic cohort of 14 patients treated with allopurinol indicated the superiority of rasburicase over allopurinol in prophylaxis and treatment of hyperuricemia in children with leukemia and lymphoma. Both authors contributed equally to this work. The study of the investigational new drug was approved and it was provided by Sanofi-Synthelabo Inc., Budapest, Hungary. This work was supported by the grant of the Health Science Council of the Ministry of Health, Republic of Hungary (ETT) No. 225.     

Bendamustine pharmacokinetic profile and exposure–response relationships in patients with indolent non-Hodgkin’s lymphoma

Purpose

The pharmacokinetic profiles of bendamustine and active metabolites were defined in patients with rituximab-refractory, relapsed indolent B-cell non-Hodgkin’s lymphoma, and supported understanding of exposure–response relationships for efficacy and safety.

Methods

Bendamustine was administered as a 60-min 120 mg/m² intravenous infusion on days 1 and 2 of six 21-day cycles. Pharmacokinetic models were developed, with covariate assessment. Correlations between bendamustine exposure and responder status or occurrence of neutropenia, thrombocytopenia, fatigue, nausea, and vomiting were examined.

Results

Following a single dose of bendamustine HCl, concentrations declined in a triphasic manner, with rapid distribution, intermediate, and slow terminal phases. The intermediate t _1/2 (40 min) was considered the pharmacologically relevant (beta elimination) t _1/2 since the initial phases accounted for 99% of the AUC. Age, sex, mild/moderate renal, or mild liver impairment did not alter pharmacokinetics. Metabolite concentrations were low relative to parent. No correlation was observed between exposure and safety or efficacy measures because of the limited range of exposures after 120 mg/m² administration, except bendamustine C _max was a significant (P value = 0.013) predictor of the probability of nausea in patients, most of whom were pretreated with antiemetics.

Conclusions

The BSA-based dosing regimen for bendamustine achieved the targeted exposure and was associated with a high incidence of therapeutic response. Given the short t _1/2 and low concentrations of bendamustine observed by 12 h after dosing, the single-dose profile for bendamustine described by these analyses is expected to be representative of the multiple-dose profile. The occurrence of nausea was significantly related to bendamustine exposure, with the probability of nausea increasing as bendamustine C _max increases.