Effect of induction chemotherapy and tandem cycles of high-dose chemotherapy on outcomes in autologous stem cell transplant for metastatic breast cancer

We assessed the effect standard-dose induction chemotherapy and tandem cycles of high-dose chemotherapy (HDC) have on outcomes in metastatic breast cancer. One hundred and one women with metastatic breast cancer were enrolled in two non-randomized phase II studies. The first group of 64 patients (induction group) received four cycles of docetaxel 75 mg/m2 and doxorubicin 50 mg/m2. The next 37 patients did not receive induction (no induction group). Both groups received two (tandem) cycles of HDC. Blood-derived stem cells were collected after the first HDC cycle, processed using CD34+ cell selection and then reinfused after the second HDC cycle. Outcomes were compared between the two groups and also to patients participating in the Philadelphia (inter-group) randomized metastatic breast cancer transplant trial (PBT-01). Intent-to-treat analysis revealed no significant differences in complete response rates (37.5% vs 27%; P = 0.20), overall response (75% vs 71%), median progression free survival (PFS) (11.9 vs 8 months; P = 0.24) and overall survival (OS) (>36 vs 25 months; P = 0.16), in the induction vs no induction groups, respectively. Adjusting for differences in known baseline characteristics, induction group patients were found to have significantly longer PFS (P = 0.002), OS (P = 0.01) and more frequent conversion from a partial to complete response (58% vs < or = 13%, P < or = 0.0002) when compared with PBT-01 patients. Induction chemotherapy administered prior to tandem cycles of HDC does not appear to adversely affect outcomes in metastatic breast cancer patients. Outcomes in our induction group also compare favorably with those observed in PBT-01 and warrant further clinical investigation.     

Selective drug‐eluting stent implantation for high‐risk patients with acute ST‐elevation myocardial infarction: Rationale and safety

Background : A selective policy of drug‐eluting stent (DES) implantation in ST‐elevation myocardial infarction (STEMI) patients at high risk of restenosis may maximize the benefit from restenosis reduction and minimize risk from late stent thrombosis (LaST). Objectives : We sought to prospectively determine the safety of selective DES implantation for long lesions (>20 mm), small vessels (<2.5 mm) and diabetic patients in patients with STEMI using a prospective single‐center registry. Methods : A total of 252 patients who underwent primary PCI between January 2005 and December 2006 were included: 126 consecutive patients receiving DES were compared with 126 age‐, sex‐, and vessel‐matched controls with STEMI who received bare‐metal stents. Composite major adverse cardiovascular events (MACE) (death, AMI, and target vessel revascularization) were used as the primary outcome measure. Results : Baseline clinical and angiographic characteristics and outcomes were similar between groups except for the prespecified diabetes, lesion length, and maximum stent diameter. Long‐term outcomes at a median follow up of 34 ± 6 months showed significant reductions in reinfarction (2% vs. 11%, P = 0.03), target vessel revascularization (TVR) (10% vs. 24%, P = 0.02), and composite MACE (18% vs. 31%, P = 0.03) with DES, with no excess of death (9% vs. 7%, P = NS) or LaST (2% vs. 1%, P = NS). In a Cox multivariate model, clopidogrel cessation at long‐term follow‐up was the most powerful predictor of hierarchical MACE (HR: 5.165; 95%CI: 2.019–13.150, P = 0.001). Conclusions : Selective DES implantation in patients with high‐risk STEMI appears safe, and exposes fewer patients to the risk of LaST. A randomized comparison of selective versus routine DES use in patients with STEMI should be considered. © 2010 Wiley‐Liss, Inc.     

Intermittent granulocyte colony-stimulating factor maintains dose intensity after ABVD therapy complicated by neutropenia

Introduction: Granulocyte Colony‐Stimulating Factor (G‐CSF) is commonly used to maintain dose intensity in patients receiving ABVD chemotherapy (doxorubicin, bleomycin, vinblastine and dacarbazine) for Hodgkin lymphoma. However, the need for growth factor support is unclear, with studies suggesting that dose intensity can be maintained without G‐CSF. Moreover, G‐CSF is expensive (pegfilgrastim: EUR 1540/cycle; 300 μg filgrastim for 7 days: EUR 700/cycle) and is associated with side effects including bone pain and increased risk of bleomycin lung toxicity. Intermittent G‐CSF may be an effective compromise, given that the effect of G‐CSF on granulocyte precursors in vitro persists for 4–5 days after administration. After promising results of a pilot study, this schedule has been used subsequently in the majority of our patients receiving G‐CSF as secondary prophylaxis for ABVD complicated by neutropenia. Methods: Retrospective analysis of the incidence of febrile neutropenia and treatment delay in a variety of different G‐CSF schedules used as secondary prophylaxis in patients receiving ABVD. Results: 848 cycles in 85 consecutive patients were evaluated. Most patients (86%) received G‐CSF, generally commenced prophylactically for neutropenia when cycle 1B was due. Intermittent G‐CSF (typically given on days 4, 8 and 12) was used in 413 cycles compared with daily or pegylated G‐CSF in 99 cycles. In patients receiving intermittent G‐CSF, the median neutrophil count, across all cycles, was 7.3 × 10⁹/L (range: 1.4–47.1) when the next scheduled chemotherapy was due. There were two cases of febrile neutropenia (0.45%) and no treatment delays. One patient developed possible bleomycin toxicity. Conclusions: Intermittent G‐CSF is effective in maintaining dose intensity in patients receiving ABVD.     

Add‐on treatment with intermediate‐acting insulin versus sliding‐scale insulin for patients with type 2 diabetes or insulin resistance during cyclic glucocorticoid‐containing antineoplastic chemotherapy: a randomized crossover study

The aim of this study was to compare the effectiveness and safety of intermediate‐acting insulin (IMI) titrated on body weight and glucocorticoid dose with that of short‐acting sliding‐scale insulin (SSI) in patients on recurrent high‐dose glucocorticoid‐containing chemotherapy. We enrolled 26 patients with type 2 diabetes mellitus or random blood glucose level >12 mmol/l in a previous cycle of chemotherapy in a randomized crossover study. In two consecutive cycles of glucocorticoid‐containing chemotherapy, participants were treated with either IMI or SSI, as add‐on to routine diabetes medication. We compared time spent in target range (3.9–10 mmol/l), measured by continuous glucose monitoring (CGM), and the occurrence of hypoglycaemia. IMI resulted in a higher proportion of glucose values within target range than SSI (34.4 vs 20.9%; p < 0.001). There were no severe or symptomatic hypoglycaemic events. Two participants in each group had a subclinical hypoglycaemia detected only by CGM. Once‐daily IMI resulted in better glycaemic control than SSI in patients with glucocorticoid‐induced hyperglycaemia during chemotherapy. Safety was not compromised as the incidence of hypoglycaemia was low and not different between both regimens.     

Low incidence of pneumocystis pneumonia utilizing PCR‐based diagnosis in patients with B‐cell lymphoma receiving rituximab‐containing combination chemotherapy

Recent literature has demonstrated concern over the risk of Pneumocystis jirovecii pneumonia (PJP) when administering rituximab with combination chemotherapy such as in R‐CHOP; however, the exact risk and potential need for prophylaxis is unknown. We sought to determine the incidence of PJP infection following R‐CHOP administration in patients with B‐cell lymphoma. Consecutive patients diagnosed with B‐cell lymphoma receiving R‐CHOP were evaluated from chemotherapy initiation until 180 days after the last administration. The primary outcome was cumulative incidence of PJP infection. Secondary endpoints included the association of rituximab, prednisone and subsequent chemotherapy with PJP infection risk. A total of 689 patients (53% male, median age 66 years) were included. Seventy‐three percent of patients completed at least 6 cycles of R‐CHOP treatment. Median rituximab and prednisone cumulative doses were 3950 mg and 5325 mg, respectively. Median daily prednisone dose through end of treatment was 45 mg (range 7.6 mg to 119 mg). The cumulative incidence of PJP was 1.51% (95% CI 0.57–2.43, at maximum follow‐up of 330 days), below 3.5%, the conventional threshold for prophylaxis. Univariate analysis did not detect a statistically significant association between PJP and rituximab, steroids, or receipt of additional chemotherapy in this patient population. Our results demonstrate a low occurrence of Pneumocystis pneumonia during R‐CHOP treatment of B‐cell lymphoma and argue against universal anti‐Pneumocystis prophylaxis in this setting. Further investigations should focus on targeted anti‐Pneumocystis prophylaxis for patients presenting with high‐risk baseline characteristics or when receiving rituximab‐inclusive intensive combination chemotherapy regimens as treatment for other aggressive lymphoma subtypes. Am. J. Hematol. 91:1113–1117, 2016. © 2016 Wiley Periodicals, Inc.     

Inferior outcome after allogeneic transplant in first remission in high‐risk AML patients who required more than two cycles of induction therapy

While some patients with high‐risk acute myeloid leukemia (AML) require one or two cycles of induction chemotherapy to achieve a complete remission (CR), others require more than two cycles. We examined the outcomes of patients with high‐risk AML who received allogeneic HPC transplant in CR1. Forty five consecutive high‐risk AML patients in CR1 were included. All 45 patients had adverse cytogenetics, FLT 3 mutations, or secondary AML. Group A patients (n = 33) received one or two cycles, and Group B (n = 12) three or more cycles of induction chemotherapy. The patients were comparable in age, sex, white cell count at presentation, and time from diagnosis and from last chemotherapy to transplant. The 100‐day mortality rate was higher in Group B patients (50% vs. 9%, P = 0.006). They had a higher non‐relapse mortality (33% vs. 6%, P = 0.035) and a longer length of hospital stay from the day of stem cell infusion (median 21 vs. 20, P = 0.02; third quartile 22 vs. 28, P = 0.02). There was also a trend toward inferior event‐free survival and overall survival. High‐risk AML patients undergoing allogeneic transplant in CR1 after three or more cycles of induction chemotherapy have an inferior outcome and higher mortality when compared to those who only needed one or two cycles of induction chemotherapy. Novel strategies are needed to reduce the transplant‐related mortality in high‐risk AML patients needing more than two cycles of induction chemotherapy prior to allogeneic transplant in CR1. Am. J. Hematol. 90:715–718, 2015. © 2015 Wiley Periodicals, Inc.     

Patient‐reported health‐related quality of life from the phase III TOURMALINE‐MM1 study of ixazomib‐lenalidomide‐dexamethasone versus placebo‐lenalidomide‐dexamethasone in relapsed/refractory multiple myeloma

TOURMALINE‐MM1 is a phase III, randomized, double‐blind, placebo‐controlled study of ixazomib plus lenalidomide and dexamethasone (IRd) versus placebo‐Rd in patients with relapsed/refractory multiple myeloma following 1–3 prior lines of therapy. The study met its primary endpoint, demonstrating significantly longer progression‐free survival (PFS) in the IRd arm versus placebo‐Rd arm (median 20.6 vs 14.7 months, hazard ratio 0.74, P = .01), with limited additional toxicity. Patient‐reported health‐related quality of life (HRQoL) was a secondary endpoint of TOURMALINE‐MM1. The European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core‐30 (QLQ‐C30) and Multiple Myeloma Module 20 (QLQ‐MY20) were completed at screening, the start of cycles 1 and 2, every other cycle, the end of treatment, and every 4 weeks until progression. Over median follow‐up of 23.3 and 22.9 months in the IRd and placebo‐Rd arms, mean QLQ‐C30 global health status (GHS)/QoL scores were maintained from baseline over the course of treatment in both groups, with no statistically significant differences between groups. EORTC QLQ‐C30 function domain scores were also generally maintained from baseline; similarly, physical, emotional, and social function domains were maintained with IRd versus placebo‐Rd, with slightly higher mean change from baseline scores at earlier time points with IRd. Findings from this double‐blind study demonstrate that addition of ixazomib to Rd significantly improved efficacy while HRQoL was maintained, reflecting the limited additional toxicity seen with IRd versus placebo‐Rd, and support the feasibility of long‐term IRd administration.     

A phase II study of two cycles of high-dose chemotherapy with autologous stem cell support in patients with metastatic breast cancer who meet eligibility criteria for a single cycle

Multi-cycle high-dose chemotherapy with autologous stem cell support (HDC-ASCS) may improve the results obtained with single-cycle HDC-ASCS in metastatic breast cancer (MBC). However, the tolerability and efficacy of additional cycles of HDC-ASCS in patients selected using standard eligibility criteria for single cycle HDC-ASCS is uncertain. Twenty-nine patients with MBC and a CR or PR to induction chemotherapy were selected by standard institutional eligibility criteria for single-cycle HDC-ASCS. Cycle 1 HDC-ASCS (cyclophosphamide 6 g/m2; mitoxantrone 70 mg/m2; carboplatin 800 mg/m2) was followed by a planned second cycle (etoposide 1.6 g/m2; thiotepa 800 mg/m2; carboplatin 800 mg/m2 modulated by tamoxifen 120 mg/m2/day x 5 days) with a median interval of 3.2 months. CR rate was 20% after induction chemotherapy and 33% and 54% after HDC cycles I and II, respectively. Sixteen patients (55%) failed to complete HDC cycle II within 200 days because of disease progression, toxicity, inadequate stem cell collection, insurance denials or patient choice. Median progression-free survival (PFS) for all 29 patients entered is 301 days from date of HDC cycle I and actuarial PFS at 2 years is 35%. For the 13 patients who received the two cycles of HDC-ASCS, actuarial PFS at 2 years was 54% (P = NS compared to those receiving only one cycle). These data show that a second cycle of full-dose intensity HDC-ASCS may increase the proportion of patients with MBC that achieve CR and may increase PFS. However, a large proportion of patients that complete HDC-ASCS cycle I may fail to proceed to cycle II in a timely fashion. Bone Marrow Transplantation (2000) 25, 519-524.     

Adding insulin glargine vs. NPH insulin to metformin results in a more efficient postprandial β‐cell protection in individuals with type 2 diabetes

Aim: Postprandial release of intact proinsulin (IP) is an independent marker for β‐cell dysfunction in patients with type 2 diabetes. This open‐label, parallel‐group, two‐arm, pilot study compared the β‐cell protective effect of adding insulin glargine (GLA) vs. NPH insulin to ongoing metformin. Material and methods: Overall, 28 insulin‐naive type 2 diabetes subjects (mean ± SD age, 61.5 ± 6.7 years; diabetes duration, 9.8 ± 6.5 years; HbA1c, 7.1 ± 0.5%; BMI, 30.7 ± 4.3 kg/m²) treated with metformin and sulfonylurea were randomized to add once‐daily GLA or NPH at bedtime. At baseline and after 3 months, subjects received a standardized breakfast, lunch and dinner, with pre‐ and postprandial blood sampling to measure plasma IP, total insulin and blood glucose (BG). Results: Insulin dose after 3 months was comparable in both groups (GLA vs. NPH: 23.6 ± 13.4 vs. 23.3 ± 12.7; p = NS ). Both treatments significantly reduced fasting BG levels (GLA: 158 ± 19 to 121 ± 23 mg/dl; NPH: 156 ± 34 to 119 ± 29 mg/dl; both p < 0.01 vs. baseline). Fasting and postprandial BG levels did not differ between groups. IP levels decreased in both groups (p < 0.05 at all timepoints). Although IP release after breakfast did not differ between treatments, GLA induced a greater reduction in IP release after lunch (p = 0.08) and dinner (p = 0.04). Total plasma insulin levels did not differ between groups. Conclusions: Adding basal insulin to metformin reduces postprandial β‐cell load. While GLA and NPH had comparable effects at breakfast, GLA reduces β‐cell stress more effectively at dinner, and with a trend at lunch, most probably because of its longer lasting pharmacodynamic profile.     

Favourable outcomes of poor prognosis diffuse large B‐cell lymphoma patients treated with dose‐dense Rituximab,high‐dose Methotrexate and six cycles of CHOP‐14 compared to first‐line autologous transplantation

The optimal therapeutic approach for young diffuse large B‐cell lymphoma (DLBCL) patients with high‐intermediate and high‐risk age‐adjusted international prognostic index (aaIPI) remains unknown. Hereby we report a 10‐year single‐centre study of 63 consecutively treated patients. To optimize outcome, two approaches were carried out: Cohort 1 patients received four cycles R‐CHOP‐21 (rituximab, cyclophosphamide, daunorubicin, vincristine, prednisolone over 21 days) followed by first‐line high‐dose chemotherapy with autologous stem‐cell support (HDCT‐ASCT), resulting in 2‐year progression‐free (PFS) and overall survival (OS) of 60·6% and 67·9%. 39·4% of those patients were not transplanted upfront, mainly due to early progressive disease (24·2%). Cohort 2 patients received an early intensified protocol of six cycles of CHOP‐14 (cyclophosphamide, daunorubicin, vincristine, prednisolone over 14 days) with dose‐dense rituximab and high‐dose methotrexate resulting in promising overall response‐ (93·3%) and complete remission (90%) rates and sustained survival (2‐year PFS and OS: 93·3%). In an intention‐to‐treat analysis, 2‐year PFS (60·6% vs. 93·3%, hazard ratio [HR] 7·2, P = 0·009) and OS (69·7% vs. 93·3%, HR 4·95, P = 0·038) differed significantly, in favour of the early intensified protocol (Cohort 2). In a multivariate Cox‐regression model, PFS (HR 8·12, 95% confidence interval [CI] 1·83–35·9, P = 0·006) and OS (HR 5·86, 95% CI 1·28–26·8, P = 0·02) remained superior for Cohort 2 when adjusted for aaIPI3 as the most important prognostic factor. Survival of young poor‐prognosis DLBCL patients appears superior after early therapy intensification.     

Oxidative stress in non‐small cell lung cancer patients after chemotherapy: Association with treatment response

Background and objective: The aim of this study was to assess the level of oxidative stress after chemotherapy in non‐small cell lung cancer patients, and its association with treatment response and survival. Methods: Two hundred and three previously untreated non‐small cell lung cancer patients and 150 healthy subjects were selected for the study. Patients received cisplatin + etoposide, and were followed for up to six cycles, for evaluation of oxidative stress. Blood levels of lipid peroxidation products (LPO), glutathione (GSH) and nitric oxide (NO), and superoxide dismutase (SOD) activity were measured at day 0 and after the third and sixth cycles of chemotherapy. Response and survival were measured at the end of follow up. Survival was estimated by the Kaplan–Meier method using the log–rank test. Results: In the patients, pretreatment levels of LPO and NO were low, while GSH and SOD levels were high compared with those after the third and sixth cycles of chemotherapy. Among the 203 patients, there were 51 deaths, 82 non‐responders and 70 responders at the end of the sixth cycle. Overall mean survival was higher among responders than non‐responders (24.6 vs 21.2 weeks, P < 0.01). The hazard ratio was 2.4 (95% CI: 1.3–3.77). Pretreatment levels of oxidative stress were similar among responders and non‐responders (P > 0.05). After the third and sixth cycles of chemotherapy, LPO and NO levels were low (P < 0.05 or P < 0.01) and GSH levels and SOD activity were high (P < 0.05 or P < 0.01) in responders as compared with non‐responders. Conclusions: In lung cancer patients, oxidative stress increased and anti‐oxidant enzymes decreased as the disease progressed. Chemotherapy may suppress oxidative stress and decreased anti‐oxidant enzyme activity in responders as compared with non‐responders. These effects may contribute to improved survival among responders.     

Drug‐eluting stents versus bare‐metal stents for treatment of bare‐metal in‐stent restenosis

Objectives : We compared the long‐term outcomes of drug‐eluting stents (DES) versus bare‐metal stents (BMS) for treatment of bare‐metal in‐stent restenosis (ISR). Background : There are no randomized trials or observational studies directly comparing the safety and efficacy of DES versus BMS for treatment of bare‐metal ISR. Methods : We examined data on all patients who underwent percutaneous coronary intervention (PCI) for ISR at Cleveland Clinic between 05/1999 and 06/2007. We compared the efficacy and safety of DES to BMS for treating bare‐metal ISR. The primary end point was a composite of death, myocardial infarction (MI), or target lesion revascularization (TLR). The secondary endpoints were individual components of the primary endpoint. Results : Of the 931 patients identified over 8 years, 706 had bare‐metal ISR and met our study criteria. Of the 706 patients with bare‐metal ISR, 362 were treated with DES and 344 with BMS. There were 230 cumulative events for a median follow‐up of 3.2 years. After adjusting for 27 variables, DES were associated with lower primary endpoint compared to BMS for treatment of bare‐metal ISR (21% vs. 45%, adjusted hazard ratio [HR] 0.63; 95% confidence interval [CI], 0.42–0.95; P = 0.03). The individual secondary endpoint of death (8% vs. 24%, P = 0.005) favored DES, but MI (3% vs. 8%, P = 0.31), and TLR (13% vs. 20%, P = 0.23) failed to reach statistical significance. Conclusions : In our multivariate analysis of patients with bare‐metal ISR, DES use was associated with significantly lower death, MI, or TLR when compared to BMS. © 2010 Wiley‐Liss, Inc.     

RB but not R‐HCVAD is a feasible induction regimen prior to auto‐HCT in frontline MCL: results of SWOG Study S1106

Aggressive induction chemotherapy followed by autologous haematopoietic stem cell transplant (auto‐HCT ) is effective for younger patients with mantle cell lymphoma (MCL ). However, the optimal induction regimen is widely debated. The Southwestern Oncology Group S1106 trial was designed to assess rituximab plus hyperCVAD /MTX /ARAC (hyperfractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone, alternating with high dose cytarabine and methotrexate) (RH ) versus rituximab plus bendamustine (RB ) in a randomized phase II trial to select a pre‐transplant induction regimen for future development. Patients had previously untreated stage III , IV , or bulky stage II MCL and received either 4 cycles of RH or 6 cycles of RB , followed by auto‐HCT . Fifty‐three of a planned 160 patients were accrued; an unacceptably high mobilization failure rate (29%) on the RH arm prompted premature study closure. The estimated 2‐year progression‐free survival (PFS ) was 81% vs. 82% and overall survival (OS ) was 87% vs. 88% for RB and RH , respectively. RH is not an ideal platform for future multi‐centre transplant trials in MCL . RB achieved a 2‐year PFS of 81% and a 78% MRD negative rate. Premature closure of the study limited the sample size and the precision of PFS estimates and MRD rates. However, RB can achieve a deep remission and could be a platform for future trials in MCL .     

COMPARISON OF ULTRAFLEX AND NITI‐S STENTS FOR PALLIATION OF UNRESECTABLE MALIGNANT GASTRODUODENAL OBSTRUCTION

Aim: Self‐expandable metallic stents are widely used for palliation of malignant gastric outlet obstruction (GOO), but clinical outcomes of different stents have not been compared. Here, we compared outcomes in patients with a GOO receiving either an Ultraflex (UF) or a Niti‐S (NS) stent. Methods: Prospective outcomes in 53 patients receiving palliative placement of an NS stent for symptomatic GOO over a 3‐year period were compared with those obtained retrospectively in 31 patients receiving a UF stent in a previous 5‐year period. Main outcome measurement was between‐group comparison of clinical outcome, complications, and reintervention. Results: Baseline characteristics between the groups were comparable. No difference in technical or clinical success rate was observed. Median procedure time for NS placement was shorter than for UF (15 vs 40 min; P < 0.0001). Complications were more frequent with NS than with UF placement, albeit without statistical significance (16% vs 25%). Although two severe complications occurred in each group, neither was stent related in the NS group. Reintervention was more frequent in the NS group (3% vs 21%; P = 0.0485). Median survival time was 53 versus 88 days for UF versus NS stents, respectively. Conclusion: Although no significant difference was seen with regard to feasibility, reintervention was less frequent with UF stents than with NS stents. However, UF stents require much more procedure time, and a complicated and difficult placement procedure. These observations suggest that although NS stents placed using a through‐the‐scope technique may be more patient friendly than UF stents, further optimization of through‐the‐scope stents is still required. Further prospective comparison of NS and UF stents in GOO treatment is warranted.     

A short course of induction chemotherapy followed by two cycles of high-dose chemotherapy with stem cell rescue for chemotherapy naive metastatic breast cancer

A single cycle of high-dose chemotherapy with stem cell support (HDC) in women with responsive metastatic breast cancer (BC) consistently achieves over 50% complete and near complete response (CR/nCR). This significant cytoreduction results in a median event-free survival (EFS) of 8 months, and approximately 20% 3-year and 16% 5-year EFS in selected patients. To improve long-term outcomes, new strategies to treat minimal residual tumor burden are needed. Increased total dose delivered can be achieved with two cycles of HDC. Critical design issues include shortening induction chemotherapy to avoid development of drug resistance and the use of different agents for each HDC cycle. We have determined the maximum tolerated dose (MTD) for paclitaxel combined with high-dose melphalan in the context of a double transplant and explored the impact of a short induction phase. Between June 1994 and August 1996, we enrolled 32 women with metastatic BC on to this phase I double transplant trial. Induction consisted of doxorubicin 30 mg/m2/day days 1-3 given for 2 cycles every 14 days with G-CSF 5 microg/kg s.c. days 4-12. Stem cell collection was performed by leukapheresis in each cycle when the WBC recovered to above 1000/microl. Patients with stable disease or better response to induction were eligible to proceed with HDC. HDC regimen I (TxM) included paclitaxel with dose escalation from 0 to 300 mg/m2 given on day 1 and melphalan 180 mg/m2 in two divided doses given on day 3. HDC regimen II was CTCb (cyclophosphamide 6 g/m2, thiotepa 500 mg/m2, and carboplatin 800 mg/m2 total doses) delivered by 96-h continuous infusion. At the first dose level of 150 mg/m2 paclitaxel by 3 h infusion, four of five patients developed dose-limiting toxicity consisting of diffuse skin erythema and capillary leak syndrome. Only two of these five completed the second transplant. Subsequently, paclitaxel was delivered by 24-h continuous infusion together with 96 h of dexamethasone and histamine receptor blockade. This particular toxicity was not observed again. No toxic deaths occurred and dose-limiting toxicity was not encountered. Three patients were removed from study prior to transplant: one for insurance refusal and two for disease progression. All others completed both cycles of transplant. Complete and near complete response (CR/nCR) after completion of therapy was achieved in 23 (72%) of 32 patients. The median EFS is 26 months. The median overall survival has not yet been reached. At a median follow-up of 58 months, EFS and overall survival are 41% and 53%, respectively. This double transplant approach is feasible, safe, and tolerable. Treatment duration is only 14 weeks and eliminates lengthy induction chemotherapy. The observed event-free and overall survivals are promising and are better than expected following a single transplant. Whilst selection biases may in part contribute to this effect, a much larger phase II double transplant trial is warranted in preparation for a potential randomized comparison of standard therapy vs single vs double transplant.     

Intensive consolidation with G‐CSF support: Tolerability,safety, reduced hospitalization,and efficacy in acute myeloid leukemia patients ≥60 years

The aim of this study was to evaluate the efficacy and feasibility of intensified consolidation therapy employing fludarabine and ARA‐C in cycle 1 and intermediate‐dose ARA‐C (IDAC) in cycles 2 through 4, in elderly acute myeloid leukemia (AML) patients and to analyze the effects of pegfilgrastim on the duration of neutropenia, overall toxicity, and hospitalization‐time during consolidation in these patients. Thirty nine elderly patients with de novo AML (median age 69.9 years) who achieved complete remission (CR) after induction‐chemotherapy were analyzed. To examine the effect of pegfilgrastim on neutropenia and hospitalization, we compared cycles 2 and 4 where pegfilgrastim was given routinely from day 6 (IDAC‐P) with cycle 3 where pegfilgrastim was only administered in case of severe infections and/or prolonged neutropenia. All four planned cycles were administered in 23/39 patients (59.0%); 5/39 patients (12.8%) received 3 cycles, 3/39 (7.7%) 2 cycles, and 8/39 (20.5%) one consolidation‐cycle. The median duration of severe neutropenia was 7 days in cycle 2 (IDAC‐P), 11.5 days in cycle 3 (IDAC), and 7.5 days in cycle 4 (IDAC‐P) (P < .05). Median overall survival was 1.1 years and differed significantly between patients aged <75 and ≥75 years (P < .05). The probability to be alive after 5 years was 32%. Together, intensified consolidation can be administered in AML patients ≥60, and those who are <75 may benefit from this therapy. Routine administration of pegfilgrastim during consolidation shortens the time of neutropenia and hospitalization in these patients.     

Long‐term followup of health status in patients with severe rheumatoid arthritis after high‐dose chemotherapy followed by autologous hematopoietic stem cell transplantation

Objective

High‐dose chemotherapy (HDC) followed by autologous hematopoietic stem cell transplantation (HSCT) is a new treatment for patients with severe, refractory rheumatoid arthritis (RA). The present study was undertaken to assess the health status of patients with severe RA over a long‐term followup period after treatment with HDC + HSCT.

Methods

Health status and utility scores were assessed in 8 patients before and after treatment with HDC + HSCT. Patients were followed up for 5 years posttransplantation. Health status was assessed by the Health Assessment Questionnaire (HAQ), the RAND‐36 version of the Short Form 36 (SF‐36) health survey, and the Arthritis Impact Measurement Scales (AIMS). Utility scores were calculated using the EuroQol (EQ‐5D) questionnaire and the SF‐36–derived utility index (called the SF‐6D), from which quality‐adjusted life years (QALYs) were derived.

Results

Most measures of health status improved compared with baseline in the first 2 years posttransplantation, notably HAQ and AIMS scores and scores on the functional status, general health, and health change summary scales of the RAND‐36 version of the SF‐36. Utility scores derived from the EQ‐5D questionnaire and the SF‐6D also increased significantly after transplantation. This was reflected in the 0.28 QALYs gained compared with baseline. For a putative 50‐year‐old RA patient with a life expectancy of 20 years, a threshold analysis revealed that HDC + HSCT yielded more QALYs than conventional therapy when treatment‐related mortality (TRM) was <2.8%.

Conclusion

HDC + HSCT temporarily increased the functionality and health status of patients with severe, refractory RA. With a reported TRM of 1.3%, HDC + HSCT can be considered a realistic treatment option for patients with severe RA.

     

High dose chemotherapy followed by autologous peripheral blood stem cell transplantation or conventional pharmacological treatment for refractory rheumatoid arthritis? A Markov decision analysis

OBJECTIVE: To evaluate the effect of high dose chemotherapy (HDC) followed by autologous hematopoietic stem cell transplantation (ASCT) in comparison to conventional pharmacological therapy in the treatment of patients with refractory, progressively erosive rheumatoid arthritis (RA). METHODS: Decision analysis using a Markov model with a 5.5 year time horizon. Probabilities of transition towards 5 different health states, ranging from 70% improvement to death, were derived from published case reports, patient series, and expert panels. Quality of life (QOL) estimates were obtained from 2 RA clinical trials. Patients were hypothetical cohorts of 50-year-old female patients with progressively erosive, active RA, who failed treatment with methotrexate, combination therapy, and tumor necrosis factor blocking agents. Interventions were HDC + ASCT versus conventional pharmacological treatment with a (combination) therapy of disease modifying antirheumatic drugs. As main outcome measures, we included the number of quality adjusted life years (QALY) after HDC + ASCT compared to conventional therapy. Sensitivity analysis was performed to investigate the influence of treatment related mortality (TRM) and the influence of QOL during HDC + ASCT, and to assess the minimal desired effectiveness of HDC + ASCT for a given TRM of 1% and 10%. RESULTS: HDC + ASCT and conventional pharmacological treatment were equally effective in the base-case analysis (3.48 vs 3.46 QALY). A TRM of less than 3.3% favored HDC + ASCT as the preferred treatment. The analysis showed that when TRM was set at 1%, a relatively short period of efficacy was sufficient to remain the preferred strategy, whereas a TRM of 10% would require a sustained response for several years. CONCLUSION: This model predicted equally favorable effects of HDC + ASCT and conventional therapy in the treatment of refractory RA in the base-case. The minor differences in terms of QALY seem to indicate that clinical decision making should be guided by patient preferences. However, better clinical efficacy might be achieved by adaptation of the treatment regimen of HDC + ASCT and patient selection. The model supports the need for randomized clinical trials and may contribute to an optimal study design.     

A phase III randomized trial of high‐dose CEOP + filgrastim versus standard‐dose CEOP in patients with non‐Hodgkin lymphoma: 10‐year follow‐up data: Australasian Leukaemia and Lymphoma Group (ALLG) NHL07 trial

Increasing dose intensity (DI) of chemotherapy for patients with aggressive non‐Hodgkin lymphoma (NHL) may improve outcomes at the cost of increased toxicity. This issue was addressed in a randomized trial aiming to double the DI of myelosuppressive drugs. Between 1994 and 1999, 250 patients with previously untreated aggressive NHL were randomized to treatment with six cycles of 3‐weekly standard (s) or intensive (i) chemotherapy: s‐CEOP–cyclophosphamide 750, epirubicin 75, vincristine 1.4 mg/m² all on day 1, and prednisolone 100 mg days 1–5; i‐CEOP–cyclophosphamide 1,500, epirubicin 150, vincristine 1.4 mg/m² all on day 1, and prednisolone 100 mg days 1–5. Primary endpoint was 5‐year overall survival (OS). Relative to s‐CEOP patients, i‐CEOP patients achieved a 78% increase in the DI of cyclophosphamide and epirubicin. Despite this, there was no significant difference in any outcome: 5‐year OS (56.7% i‐CEOP; 55.1% s‐CEOP; P = 0.80), 5‐year progression free survival (PFS; 41% i‐CEOP; 43% s‐CEOP; P = 0.73), 5‐year time to progression (TTP; 44% i‐CEOP; 47% s‐CEOP; P = 0.72), or complete remission (CR) + unconfirmed CR (CRu) rates (53% i‐CEOP; 59% s‐CEOP; P = 0.64). Long‐term follow up at 10 years also showed no significant differences in OS, PFS, or TTP. The i‐CEOP arm had higher rates of febrile neutropenia (70 vs. 26%), hospitalisations, blood product utilisation, haematological and gastrointestinal toxicities, and lower quality of life scores during treatment, although without significant differences 6‐month later. In the treatment of aggressive NHL in the prerituximab era, increasing DI did not result in improved outcomes, while at the same time lead to increased toxicity. Am. J. Hematol. 89:536–541, 2014. © 2014 Wiley Periodicals, Inc.     

High dose chemotherapy with haematopoietic rescue in breast cancer

High dose chemotherapy (HDC) for breast cancer has been used for some 15 years. All studies demonstrate a high response rate with approximately 20% prolonged (> 3 years) disease free survival among patients who achieved complete remission (CR) following HDC. Debate about the value of HDC has centered around the issue of patient selection, including selection by chemotherapy response. Results of one randomised, published trial of HDC versus conventional dose treatment, however, demonstrate a better outcome for the HDC group with a higher CR rate and prolongation of survival. These results have been updated and continue to show a stable proportion of long term complete remitters. In the adjuvant setting one recent trial has demonstrated no benefit from HDC ‘consolidation’ in ‘high-risk’ patients. Results of a number of other studies are pending and will help to settle this issue. The article reviews issues including patient selection by prior chemotherapy response, other methods of selection, the chemotherapy regimens used and the timing of HDC. While additional and confirmatory studies are required HDC for breast cancer remains an effective treatment modality.