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.

Allogeneic stem-cell transplantation in patients with cutaneous lymphoma: updated results from a single institution.

BACKGROUND: Cutaneous T-cell lymphomas (CTCLs) and its common variants mycosis fungoides (MF) and leukemic Sézary syndrome (SS) are rare extranodal non-Hodgkin's lymphomas. Patients who present with advanced disease and large-cell transformation (LCT) are incurable with standard treatments. In this article, we report the largest single-center experience with allogeneic stem-cell transplantation (SCT) for advanced CTCL. PATIENTS AND METHODS: This is a prospective case series of 47 CTCL patients who underwent allogeneic SCT after failure of standard therapy between July 2001 and September 2013. The Kaplan-Meier method was used to estimate overall survival (OS) and progression-free survival (PFS) curves. The method of Fine and Gray was used to fit regression models to the same covariates for these cumulative incidence data. RESULTS: The Kaplan-Meier estimates of OS and PFS at 4 years were 51% and 26%, respectively. There was no statistical difference in the OS in patients who had MF alone, SS, MF with LCT, or SS with LCT. PFS at 4 years was superior in patients who had SS versus those who did not (52.4% versus 9.9%; P = 0.02). The cumulative incidences of grade 2-4 acute graft-versus-host disease (GVHD) and chronic GVHD were 40% and 28%, respectively. The cumulative nonrelapse mortality rate was 16.7% at 2 years. CONCLUSION: Allogeneic SCT may result in long-term remissions in a subset of patients with advanced CTCL. Although post-SCT relapse rates are high, many patients respond to immunomodulation and achieve durable remissions. CLINICALTRIALSGOV: NCT00506129.

Bevacizumab/high-dose chemotherapy with autologous stem-cell transplant for poor-risk relapsed or refractory germ-cell tumors.

BACKGROUND: High-dose chemotherapy (HDC) using sequential cycles of carboplatin/etoposide is curative for relapsed germ-cell tumors (GCT). However, outcomes of high-risk patients in advanced relapse remain poor. We previously developed a new HDC regimen combining infusional gemcitabine with docetaxel/melphalan/carboplatin (GemDMC), with preliminary high activity in refractory GCT. Given the high vascular endothelial growth factor expression in metastatic GCT and the synergy between bevacizumab and chemotherapy, we studied concurrent bevacizumab and sequential HDC using GemDMC and ifosfamide/carboplatin/etoposide (ICE) in patients with poor-risk relapsed or refractory disease. PATIENTS AND METHODS: Eligibility criteria included intermediate/high-risk relapse (Beyer Model), serum creatinine ≤ 1.8 mg/dl and adequate pulmonary/cardiac/hepatic function. Patients received sequential HDC cycles with bevacizumab preceding GemDMC (cycle 1) and ICE (cycle 2). The trial was powered to distinguish a target 50% 2-year relapse-free survival (RFS) from an expected 25% 2-year RFS in this population. RESULTS: We enrolled 43 male patients, median age 30 (20-49) years, with absolute refractory (N = 20), refractory (N = 17) or cisplatin-sensitive (N = 6) disease, after a median 3 (1-5) prior relapses. Disease status right before HDC was unresponsive (N = 24, progressive disease 22, stable disease 2), partial response with positive markers (PRm(+)) (N = 8), PRm(-) (N = 7) or complete response (N = 4). Main toxicities were mucositis and renal. Four patients (three with baseline marginal renal function) died from HDC-related complications. Tumor markers normalized in 85% patients. Resection of residual lesions (N = 13) showed necrosis (N = 4), mature teratoma (N = 2), necrosis/teratoma (N = 3) and viable tumor (N = 4). At median follow-up of 46 (9-84) months, the RFS and overall survival rates are 55.8% and 58.1%, respectively. CONCLUSIONS: Sequential bevacizumab/GemDMC-bevacizumab/ICE shows encouraging outcomes in heavily pretreated and refractory GCT, exceeding the results expected in this difficult to treat population. CLINICALTRIALSGOV: NCT00936936.

Clofarabine combined with busulfan provides excellent disease control in adult patients with acute lymphoblastic leukemia undergoing allogeneic hematopoietic stem cell transplantation.

We investigated the safety and early disease control data for i.v. busulfan (Bu) in combination with clofarabine (Clo) in patients with acute lymphoblastic leukemia undergoing allogeneic hematopoietic stem cell transplantation (SCT). Fifty-one patients (median age, 36 years; range, 20-64 years) received a matched sibling (n = 24), syngeneic (n = 2), or matched unrelated donor transplant (n = 25) for acute lymphoblastic leukemia in first complete remission (n = 30), second complete remission (n = 13), or active disease (n = 8). More than one-half of the patients had a high-risk cytogenetic profile, as defined by the presence of t(9;22) (n = 17), t(4;11) (n = 3), or complex cytogenetics (n = 7). Clo 40 mg/m(2) was given once daily, with each dose followed by pharmacokinetically dosed Bu infused over 3 hours daily for 4 days, followed by hematopoietic SCT 2 days later. The Bu dose was based on drug clearance, as determined by the patient's response to a 32-mg/m(2) Bu test dose given 48 hours before the high-dose regimen. The target daily area under the receiver-operating characteristic curve was 5500 µM/min for patients age <60 years and 4000 µM/min for those age ≥60 years. The regimen was well tolerated, with a 100-day nonrelapse mortality rate of 6%. With a median follow-up of 14 months among surviving patients (range, 6-28 months), the 1-year overall survival, disease-free survival, and nonrelapse mortality rates were 67% (95% confidence interval [CI], 55%-83%), 54% (95% CI, 41%-71%), and 32% (95% CI, 16%-45%), respectively. For patients undergoing SCT in first remission, these respective rates were 74%, 64%, and 25%. Our data indicate that the combination of Clo and Bu provides effective disease control while maintaining a favorable safety profile.

Preliminary results of the combination of bevacizumab and weekly Paclitaxel in advanced melanoma.

BACKGROUND: Pretreated advanced melanoma is a poor prognosis scenario with few, if any, active therapeutic options. The antibody against vascular endothelial growth factor, bevacizumab, has demonstrated increased activity in combination with chemotherapy in many tumors. We intended to evaluate the activity of the combination of weekly paclitaxel and bevacizumab in previously treated metastatic melanoma. PATIENTS AND METHODS: Patients with previously treated metastatic melanoma received paclitaxel 70 mg/m(2) weekly and bevacizumab 10 mg/kg biweekly for 5 consecutive weeks every 6 weeks. RESULTS: Twelve patients were treated. Two patients (16.6%) achieved a partial response and 7 patients (58.3%) stable disease. Responses were seen in soft tissue, lung and brain metastases. Median disease-free and overall survival times were 3.7 and 7.8 months, respectively. Treatment was well tolerated. Main toxicities were grade 3 asymptomatic lymphopenia in 6 patients, grade 3 leucopenia in 2 patients, and grade 3 thrombocytopenia in 1 patient. CONCLUSIONS: Our preliminary results suggest that the combination of bevacizumab and weekly paclitaxel is active and safe in patients with metastatic melanoma, warranting further investigation.

Early relapse after autologous hematopoietic cell transplantation remains a poor prognostic factor in multiple myeloma but outcomes have improved over time.

Duration of initial disease response remains a strong prognostic factor in multiple myeloma (MM) particularly for upfront autologous hematopoietic cell transplant (AHCT) recipients. We hypothesized that new drug classes and combinations employed prior to AHCT as well as after post-AHCT relapse may have changed the natural history of MM in this population. We analyzed the Center for International Blood and Marrow Transplant Research database to track overall survival (OS) of MM patients receiving single AHCT within 12 months after diagnosis (N=3256) and relapsing early post-AHCT (<24 months), and to identify factors predicting for early vs late relapses (24-48 months post-AHCT). Over three periods (2001-2004, 2005-2008, 2009-2013), patient characteristics were balanced except for lower proportion of Stage III, higher likelihood of one induction therapy with novel triplets and higher rates of planned post-AHCT maintenance over time. The proportion of patients relapsing early was stable over time at 35-38%. Factors reducing risk of early relapse included lower stage, chemosensitivity, transplant after 2008 and post-AHCT maintenance. Shorter post-relapse OS was associated with early relapse, IgA MM, Karnofsky <90, stage III, >1 line of induction and lack of maintenance. Post-AHCT early relapse remains a poor prognostic factor, even though outcomes have improved over time.

Primary central nervous system lymphoma treated with rituximab plus temozolomide in a second line schedule.

We report a case of primary CNS lymphoma treated with high-dose methotrexate in the first line. After disease progression the patient received cranial radiotherapy with concomitant temozolomide, followed by rituximab plus temozolomide, with complete remission of the disease maintained for at least two years and without major toxicity.

Response of resistant melanoma to a combination of weekly paclitaxel and bevacizumab.

We report here a taxol-bevacizumab-responsive metastatic melanoma case. Although the patient had been heavily pretreated for two years, she did not show any stabilisation or objective response of her disease. After treatment with taxol and bevacizumab combination an impressive response was obtained.

Fludarabine with pharmacokinetically guided IV busulfan is superior to fixed-dose delivery in pretransplant conditioning of AML/MDS patients.

We hypothesized that IV busulfan (Bu) dosing could be safely intensified through pharmacokinetic (PK-) dose guidance to minimize the inter-patient variability in systemic exposure (SE) associated with body-sized dosing, and that this should improve outcome of AML/MDS patients undergoing allogeneic stem cell transplantation. To test this hypothesis, we treated 218 patients (median age 50.7 years, male/female 50/50%) with fludarabine 40 mg/m2 once daily x4, each dose followed by IV Bu, randomized to 130 mg/m2 (N=107) or PK-guided to average daily SE, AUC of 6000 µM min (N=111), stratified for remission status and allo-grafting from HLA-matched donors. Toxicity and GvHD rates in the groups were similar; the risk of relapse or treatment-related mortality remained higher in the fixed-dose group throughout the 80-month observation period. Further, PK-guidance yielded safer disease control, leading to improved overall and PFS, most prominently in MDS patients and in AML patients not in remission at allogeneic stem cell transplantation. We conclude that AML/MDS patients receiving pretransplant conditioning treatment with our 4-day regimen may benefit significantly from PK-guided Bu dosing. This could be considered an alternative to fixed-dose delivery since it provides the benefit of precise dose delivery to a predetermined SE without increasing risk(s) of serious toxicity and/or GvHD.

Autologous hematopoietic cell transplantation for multiple myeloma patients with renal insufficiency: a center for international blood and marrow transplant research analysis.

Autologous hematopoietic cell transplantation (AHCT) in multiple myeloma (MM) patients with renal insufficiency (RI) is controversial. Patients who underwent AHCT for MM between 2008 and 2013 were identified (N=1492) and grouped as normal/mild (⩾60 mL/min), N=1240, moderate (30-59), N=185 and severe RI (<30), N=67 based on Modification of Diet in Renal Disease. Multivariate analyses of non-relapse mortality (NRM), relapse, PFS and overall survival (OS) were performed. Of the 67 patients with severe RI, 35 were on dialysis prior to AHCT. Patients received melphalan 200 mg/m2 (Mel 200) in 92% (normal/mild), 75% (moderate) and 33% (severe) RI; remainder received 140 mg/m2 (Mel 140). Thirty four of 35 patients with severe RI achieved post-AHCT dialysis independence. The 5-year PFS for normal, moderate and severe RI was 35 (95% CI, 31-38)%, 40 (31-49)% and 27 (15-40)%, respectively, (P=0.42); 5-year OS for normal, moderate and severe RI was 68 (65-71)%, 68 (60-76)% and 60 (46-74)%, respectively, (P=0.69). With moderate RI, 5-year PFS for high-dose melphalan 140 mg/m2 was 18 (6-35)% and for Mel 200 was 46 (36-57)% (P=0.009). With severe RI, 5-year PFS Mel 140 was 25 (11-41) % and for Mel 200 was 32 (11-58)% (P=0.37). We conclude that AHCT is safe and effective in patients with MM with RI.

Evaluation of the predictive value of Her-2/neu overexpression and p53 mutations in high-risk primary breast cancer patients treated with high-dose chemotherapy and autologous stem-cell transplantation.

PURPOSE: To ascertain the predictive value of Her-2/neu overexpression and p53 mutations, assessed by immunohistochemistry, in high-risk primary breast cancer (HRPBC) treated with high-dose chemotherapy (HDCT). PATIENTS AND METHODS: We obtained paraffin-embedded tumor blocks from 146 HRPBC patients previously enrolled at our program onto clinical trials of HDCT for four to nine involved axillary lymph nodes, > or = 10 involved axillary nodes, or inflammatory carcinoma. All patients received the same HDCT regimen, with cyclophosphamide, cisplatin, and carmustine (STAMP-I), followed by autologous stem-cell transplantation. Median follow-up was 42 months (range, 5 to 90 months). The same pathologist, blinded to clinical outcome, reviewed all immunostained slides. RESULTS: Positive results for Her-2/neu and p53 were found in 44.5% and 34% of the patients, respectively. Positivity for Her-2/neu was significantly associated with increased risk of relapse and death. No correlation was found between p53 mutations and relapse-free survival (RFS) or overall survival (OS). Multivariate analyses included Her-2/neu overexpression and the following variables previously identified as independent predictors of outcome in this population: tumor size, nodal ratio (number of involved nodes/number of dissected nodes), and hormone receptor status. All four variables had independent value. CONCLUSION: Her-2/neu overexpression is an independent negative predictor of RFS and OS in HRPBC treated with HDCT. Its inclusion in our previously described predictive model increases the predictive capacity of this model for the low-risk subgroup. In contrast, p53 mutations lack predictive value in this setting.

High-dose chemotherapy with autologous hematopoietic progenitor-cell support as part of combined modality therapy in patients with inflammatory breast cancer.

PURPOSE: To evaluate the feasibility of high-dose chemotherapy (HDC) with autologous hematopoietic progenitor-cell support (AHPCS) as part of combined modality therapy (CMT) in patients with inflammatory breast cancer (IBC). PATIENTS AND METHODS: From April 1993 to March 1997, 30 patients with IBC were treated at our program. Twenty-three patients received neoadjuvant chemotherapy (NAC) before HDC; 18 patients also received adjuvant chemotherapy following surgery, but before HDC. All patients received HDC with high-dose cyclophosphamide, cisplatin, and carmustine (BCNU) with AHPCS. Every patient underwent surgery either before (27 patients) or after (three patients) HDC. Patients received radiotherapy after HDC in addition to tamoxifen if their tumors were estrogen receptor-positive. RESULTS: Thirteen patients experienced grade 3 or 4 nonhematologic noninfectious toxicities. In 12 patients (40%), this represented drug-induced lung injury, which in all cases responded to a 10-week course of corticosteroids. The only treatment-related death was secondary to hemolytic-uremic syndrome (HUS). Another patient suffered grade 4 CNS toxicity, which was completely reversible. All patients engrafted promptly. Eight patients relapsed, five of whom had a poor pathologic response to NAC. Relapses were local (five patients), local plus systemic (one), or systemic only (two). Median follow-up time from diagnosis and HDC is 23.5 (range, 7 to 49) and 19 (range, 4 to 44) months, respectively. Twenty-one patients (70%; 95% confidence interval [CI], 51% to 86%) remain alive and free of disease 4 to 44 months after HDC. Median disease-free survival (DFS) and overall survival have not yet been reached. CONCLUSION: HDC as part of CMT is feasible in patients with IBC. The toxicity of this treatment program is significant, but tolerable. Despite the short follow-up duration, the promising DFS observed in this group of patients warrants randomized studies that include a HDC-containing arm in patients with IBC.

Prognostic analysis of pre-transplant peripheral T-cell levels in patients receiving an autologous hematopoietic progenitor-cell transplant.

The purpose of this study was to evaluate pre-transplant T-cell status in autologous hematopoietic progenitor-cell transplantation (HPCT) recipients. Between 1999 and 2002 we prospectively enrolled 85 autologous HPCT recipients with solid tumors (N = 50) or hematological malignancies (n = 35). Patient diagnoses included breast cancer (N = 49), non-Hodgkin's lymphoma (N = 20), myeloma (N = 11), Hodgkin's disease (N = 3), germ-cell tumor (N = 1) and amyloidosis (N = 1). Levels of CD3, CD4, CD8, memory and naïve CD4, and CD8 T-cell subsets were analyzed before autologous HPCT. Autologous HPCT recipients presented with lower pre-transplant counts of CD3, CD4, but not CD8 T cells, as compared to healthy controls. Pre-transplant CD4 T-cell levels correlated with progression-free survival (PFS) (P = 0.002) and overall survival (OS) (P = 0.05), in patients with hematologic malignancies (P = 0.02) and breast cancer (P = 0.04). Specifically, pre-transplant memory CD4 + CD45RA - CD62L - T-cell levels correlated with PFS (P = 0.01). The prognostic effects of pre-transplant CD4 and CD4 + CD45RA - CD62L - T cells were independent of tumor diagnosis, tumor stage, tumor sensitivity, and, for breast cancer patients, Her2 / neu status. Our results suggest that pre-transplant CD4 T-cell status, specifically CD4 + CD45RA - CD62L - memory T cells, correlates with the outcome of autologous HPCT recipients. These observations suggest the feasibility of prospective identification of those patients at higher risk of relapse, based on their immune status.

Autologous transplantation followed closely by reduced-intensity allogeneic transplantation as consolidative immunotherapy in advanced lymphoma patients: a feasibility study.

We report outcomes in advanced lymphoma patients (n = 32) who enrolled in a trial of prospectively planned combined autologous/reduced-intensity transplantation (RIT) (n = 25) or who received RIT shortly after prior autografting because of high relapse risk or progressive disease (n = 7). Nine patients on the autologous/RIT transplant protocol did not proceed to planned RIT because of patient choice (n = 4), disease progression (n = 3), toxicity (n = 1), or no adequate donor (n = 1). Among the 23 other patients, RIT was started a median of 59 days (range 31-123) after autologous transplant. Fifteen patients had related donors, five patients had unrelated donors, and three patients had cord blood donors. Among all patients completing RIT, the median overall survival time was 385 days (95% CI 272-792), and the median relapse-free survival time was 157 days (95% CI 119-385). At the time of reporting, six patients (26%) remain alive and three patients (13%) remain alive without relapse. The 100-day transplant-related mortality (TRM) was 9% among all patients and was 0% among matched sibling donors. Overall TRM was 43%. Tandem transplant is feasible in advanced lymphoma with low early TRM. However, practical challenges associated with the strategy were significant and high levels of late TRM due to graft-versus-host disease and infections suggest that modifications of the procedure will be needed to improve outcomes and patient retention.

Phase II trial of high-dose chemotherapy with autologous stem cell transplant for stage IV breast cancer with minimal metastatic disease.

The purpose of this study was to assess the efficacy of high-dose chemotherapy (HDC) with autologous stem cell transplant in stage IV breast cancer patients with minimal metastases. Eligible patients had (a) disease that could be resected en bloc and/or irradiated with curative intent using a single field and could, thus, be rendered as having no evidence of disease (NED); and/or (b) <5% bone marrow involvement. From September 1991 to August 1997, 40 consecutive patients were prospectively entered on the study. Pre-HDC local treatment consisted of surgery (n = 31) and radiotherapy (XRT; n = 3). All patients received HDC with cyclophosphamide, cisplatin, and 1,3-bis(2-chloroethyl)-1-nitrosourea and autologous stem cell transplant, with or without CD34 selection. Following HDC, 22 patients received XRT. Four patients died of treatment-related complications. Eighteen patients developed grade 3 nonhematological toxicities (15 lung, 2 cardiomyopathy, and 1 optic neuritis), which resolved with therapy. Within a median follow-up of 49 (15-91) months, 14 patients had relapsed. Twenty-five patients (62.5%) were alive, and 22 patients (55%) were alive and free of disease. Median event-free and overall survivals were 43 and 77 months, respectively. In the subset of patients with one metastatic site, 17 of 24 (68%) remained relapse free. Grade 2 tumors, a single metastatic site, and delivery of XRT were favorable predictors of relapse-free survival in univariate but not multivariate analyses. Inclusion of HDC, as described, in the multimodal treatment of stage IV breast cancer patients with minimal metastases is promising. These results warrant prospective randomized trials with a HDC-containing arm in this patient population.

A predictive model for relapse in high-risk primary breast cancer patients treated with high-dose chemotherapy and autologous stem-cell transplant.

High-dose chemotherapy (HDCT) is currently under evaluation for high-risk primary breast cancer (HRPBC), defined by extensive axillary nodal involvement or inflammatory breast carcinoma. Phase II studies of HDCT for HRPBC show that 30-40% of patients eventually relapse. We retrospectively reviewed 176 patients enrolled in clinical trials of HDCT for HRPBC at the University of Colorado and analyzed 23 potential predictive variables for relapse. All of the patients received the same regimen, with cyclophosphamide, cisplatin, and BCNU. Nine patients who experienced a toxic death were excluded from this analysis. The resulting predictive model was subsequently tested in an independent patient set treated at Duke University with the same HDCT regimen. Nodal ratio (number of involved nodes:number of sampled nodes), tumor size, grade, stage, estrogen receptor, progesterone receptor, and clinical inflammatory breast carcinoma correlated with risk of relapse. Nodal ratio, tumor size, and the combined estrogen receptor/progesterone receptor status were independent predictors. A scoring system using those three variables determines the risk of relapse, with a sensitivity and specificity of 60 and 90%, respectively, and a positive and negative predictive value of 65 and 88%, respectively. The differences in relapse-free survival and overall survival between high- and low-score patients were highly significant (P<0.000001). This model was subsequently validated in the Duke patient set. This model can identify two subgroups of HRPBC patients with low (12%) and high (65%) risk for recurrence after HDCT. Future research that tests new therapies will focus on those patients with a high score.