What is the role of up-front autologous stem cell transplantation in mantle cell lymphoma?

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Rituximab long-term maintenance therapy after autologous stem cell transplantation in patients with B-cell non-Hodgkin’s lymphoma

Treatment of B-cell non-Hodgkin’s lymphomas (NHL) with either Rituximab alone or in combination with cytotoxic chemotherapy has been effective without major side effects. Thus, Rituximab maintenance therapy after autologous peripheral blood stem cell transplantation (PBSCT) might represent an improvement in NHL therapy. We therefore retrospectively analyzed the efficacy and side effects of monthly long-term Rituximab maintenance therapy after PBSCT in 27 patients with NHL. In median 10 infusions of Rituximab were given after PBSCT in time intervals of 1 month. Molecular monitoring of t(14;18) was performed using nested as well as quantitative real time polymerase chain reaction (RT-PCR) based on the LightCycler technology. Side effects according to common toxicity criteria (CTC) > II did mainly affect the hematopoietic system. In total, 10 patients (37%) suffered form grade III–IV hematotoxicity. Except for two patients with cutaneous Varicella–Zoster infection no serious infectious complications (CTC grade III/IV) occurred. No patient died because of treatment-related causes. This adverse event data compared favorably to the published data. Three patients had t(14;18) nested RT-PCR positive results before Rituximab therapy and converted to negativity after Rituximab therapy. We conclude that a prolonged Rituximab maintenance therapy after PBSCT with monthly administration is reliable and safe.     

The hyper-CVAD–rituximab chemotherapy programme followed by high-dose busulfan,melphalan and autologous stem cell transplantation produces excellent event-free survival in patients with previously untreated mantle cell lymphoma

The hyper-CVAD + rituximab (R) programme consists of fractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone + R alternating with high-dose methotrexate + cytarabine (HD MTX/ARA-C) + R. This regimen, when used as initial therapy for patients under 65 years of age with previously untreated mantle cell lymphoma (MCL), results in remission rates of > 85% with a median event-free survival (EFS) of > 50 months, but with a pattern of continuous relapse out to 60 months. We performed a study of hyper-CVAD + R, followed by consolidative peripheral blood progenitor cells autograft [autologous stem cell transplant (AuSCT)] with high-dose busulfan and melphalan (Bu/Mel) conditioning, in patients with responsive disease. Thirteen patients with a median age of 54 (range = 33–61) were treated. Complete remission (CR) was achieved in 12 patients (92%) after hyper-CVAD + R and 12 completed AuSCT after Bu/Mel conditioning. One patient died during the autograft and another declined AuSCT after achieving a CR with hyper-CVAD + R. With a median follow-up from diagnosis of 36 months (range = 16–53 months), the observed 36 months overall survival and EFS are both 92% for the whole cohort. These data confirm the excellent CR rates achieved by the use of hyper-CVAD + R in patients with MCL and suggest that consolidation with Bu/Mel and AuSCT may improve durable disease control when compared to published outcomes of hyper-CVAD + R alone.     

BEAC or BEAM high-dose chemotherapy followed by autologous stem cell transplantation in non-Hodgkin’s lymphoma patients: comparative analysis of efficacy and toxicity

The treatment of choice for relapsed/refractory non-Hodgkin’s lymphoma (NHL) consists of high-dose chemotherapy (HDC) followed by autologous stem cell transplantation (ASCT). Little is known, however, regarding the comparative toxicity and efficacy of various HDC regimens applied in NHL. We have retrospectively evaluated the clinical aspects of the BCNU, etoposide, cytarabine, and cyclophosphamide (BEAC) and BCNU, etoposide, cytarabine, and melphalan (BEAM) regimens for ASCT. Between April 1994 and February 2005, 97 NHL patients underwent HDC with BEAC (N = 69) or BEAM (N = 28), followed by ASCT, at the Asan Medical Center. We matched each BEAM patient with two BEAC patients having the same International Prognostic Index. Thus, 84 patients (56 BEAC and 28 BEAM) were analyzed. Median age was 40.5years, and baseline characteristics were well balanced between the two groups. The median time to neutrophil engraftment (>500/mm³) was significantly longer with BEAC than with BEAM (12 vs 11days, P = 0.001), as was the total amount of red blood cell transfusion (6.5 vs 3.7U, P = 0.037), but the median time to platelet engraftment (>20,000/mm³) and the total amount of platelet transfusion did not differ between the two groups. BEAM patients had significantly more frequent World Health Organization grade greater than or equal to 2 diarrhea than BEAC patients (46.4 vs 19.6%, P = 0.010), but the incidence of mucositis, nausea/vomiting, and bleeding and the number of episodes of febrile neutropenia and septicemia did not differ between the two groups. Median follow-up for survivors was 33months in the BEAM group and 89months in the BEAC group. Median overall survival and median event-free survival were not reached in the BEAM group and were 7.9 (95% confidence interval [CI], 1–14.8months, P = 0.003) and 3.7months (95% CI, 0.1–7.2months, P = 0.001), respectively, in the BEAC group. BEAM appeared to be superior to BEAC for survival. Regimen-related toxicities were similar, except that BEAM was associated with more frequent but acceptable diarrhea.     

Are dynamic or fixed FDG-PET measures of disease of greater prognostic value in patients with relapsed/refractory diffuse large B-cell lymphoma undergoing autologous haematopoietic stem cell transplantation?

Positron emission tomography (PET) response assessment using the Deauville score has prognostic utility in relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) undergoing autologous stem-cell transplantation (ASCT). Improved predictive methods are required to identify patients with poor outcomes who may be better considered for other salvage options. We investigated the prognostic value of mean tumour volume (MTV) and maximum standardised uptake value (SUVmax) at pre-salvage and pre-ASCT time-points, and the quantitative changes between scans (∆MTV and ∆SUVmax). One hundred and twenty-five patients with R/R DLBCL underwent salvage immunochemotherapy and ASCT: 80 patients had pre-salvage PET and 90 had pre-ASCT PET available. With a median follow-up of 5.6 years, 5-year progression-free survival (PFS) and overall survival (OS) were 52% and 65%, respectively. For patients with PET-positive residual disease after salvage therapy, pre-ASCT MTV was a significant negative prognosticator for PFS (HR 1.19 per 100 ml, p < 0.001) and OS (HR 1.78 per 100 ml, p < 0.001). Similarly, pre-ASCT SUVmax was negatively associated with PFS (HR 1.08, p < 0.001) and OS (HR 1.08, p < 0.001). Notably, pre-salvage MTV and SUVmax and ∆MTV and ∆SUVmax were not associated with PFS or OS. In conclusion, pre-ASCT MTV and SUVmax appear to be of greater predictive value than the degree of response. Potential application may exist for PET-directed management of R/R DLBCL patients.     

Rituximab therapy increased post-transplant cytomegalovirus complications in Non-Hodgkin’s lymphoma patients receiving autologous hematopoietic stem cell transplantation

The use of monoclonal antibody, rituximab, had been reported to be associated with some severe viral infections. The inference of rituximab therapy and post-transplant cytomegalovirus (CMV) infectious complications in non-Hodgkin’s lymphoma (NHL) patients is still unclear now. From 2002 to 2005, 46 patients with relapsed indolent or high-risk aggressive B cell NHL who received rituximab (17 patients) or not (29 patients) before autologous hematological stem cell transplantation (HSCT) in one institute were retrospectively analyzed for the risk factors of CMV complications after transplantation. Pre-transplant and post-transplant CMV infectious conditions, conditioning regimens, transplant types, and post-transplant complications were recorded. Post-transplant infectious complications were followed up until 6 months after transplantation.Seventeen of 46 patients received rituximab before HSCT. Three of them suffered from CMV infection and two of them developed CMV disease. All of the patients with CMV disease recovered after ganciclovir and CMV-specific immunoglobulin therapy. Twenty-nine of 46 patients without rituximab treatment before HSCT did not have CMV complications after HSCT. The risks to develop CMV infections after autologous HSCT were higher in rituximab-treated patients (17.6% vs 0%, p = 0.045, Fisher exact test, two-sided). The risks to develop CMV diseases had higher trend with rituximab therapy than without rituximab therapy (11.7% vs 0%, p = 0.131, Fisher exact test, two-sided). The NHL patients receiving rituximab therapy had higher risk to develop CMV infectious complications after autologous HSCT.     

Weekly versus twice weekly bortezomib given in conjunction with rituximab, in patients with recurrent follicular lymphoma, mantle cell lymphoma and Waldenström macroglobulinaemia

The combination of bortezomib and rituximab was evaluated in patients with mantle cell lymphoma (MCL), follicular lymphoma (FL) and Waldenström macroglobulinaemia (WM), in a Phase I and later, a randomized Phase II study. In the randomized study, 42 patients with recurrent/refractory disease received either: bortezomib 1·3 mg/m² on days 1, 4, 8 and 11 of a 3‐week cycle with rituximab 375 mg/m² on day 1 (21 patients) or: bortezomib 1·6 mg/m² and rituximab on days 1, 8, 15 and 22 of a 5‐week cycle (with rituximab being given only in cycles 1 and 4).Twenty‐eight patients were withdrawn (toxicity 16, progression 7, and ‘patient choice’ 5). The main toxicities were neurological, gastro‐intestinal and haematological. The overall response rate was 28/42(67%) and by histology: MCL 11/19, FL 8/15, and WM 9/10. Ten of 28 responding patients remained progression‐free at 1–3·5 years. Toxicity and efficacy were equivalent between the two groups. The combination has significant toxicity but is effective, particularly in patients with WM.     

Successful autologous peripheral blood stem cell transplantation in a Jehovah’s Witness with multiple myeloma: review of literature and recommendations for high-dose chemotherapy without support of allogeneic blood products

We present a case report of a successful high-dose melphalan therapy and autologous stem cell transplantation without the use of allogeneic blood product support in a 70-year-old patient suffering from multiple myeloma. Based on the experience in this case and thorough evaluation of the literature, we consider pre-transplant Hb level of 11–12 g/dl, platelet count higher than 70/nl, good WHO performance status of two and lower and informed consent as important eligibility criteria. During cytopenia recommended supportive measures include growth factor support with erythropoietin and G-CSF, p.o. iron treatment as well as prophylactic use of anti-fibrinloytic agents. Furthermore we discuss additional options that might be considered depending on the individual factors as e.g. pre-transplant collection and cryoconservation of autologous platelet concentrates. Moreover, an analysis of socio-economic issues regarding this procedure is presented. We conclude that allogeneic blood product free transplantation is a feasible procedure that can be offered to the patients belonging to distinct religious groups refusing allogeneic blood products as Jehova′s Witnesses and patients presenting other contraindications for transfusions.     

High-dose thiotepa,etoposide and carboplatin as conditioning regimen for autologous stem cell transplantation in patients with high-risk Hodgkin’s lymphoma

Abstract

Background: Autologous stem cell transplantation (ASCT) generally provides good results in Hodgkin’s lymphoma (HL). We studied a high-dose chemotherapy regimen based on thiotepa, etoposide and carboplatin (TECA).

Methods: Fifty-eight patients with advanced HL were treated with thiotepa, etoposide and carboplatin for transplant induction.

Results: The overall response rate was 79·3% (39 CR: 67·2%; and 7 PR: 12·1%); 12 patients (20·1%) were non-responders. The 5-year overall survival rate was 77·6%; five initially responder patients relapsed within the first 5 years of follow-up and underwent salvage therapy.

Conclusion: The TECA conditioning regimen for ASCT in HL results in a good anti-HL effect, positive response to treatment and high 5-year overall survival rate. It was also well tolerated and did not induce excessive toxicity, suggesting that TECA may be a very useful conditioning regimen for HL.     

A polymorphism in NFKB1 is associated with improved effect of interferon-α maintenance treatment of patients with multiple myeloma after high-dose treatment with stem cell support

Background

Maintenance therapy with interferon-α after high-dose treatment with stem cell support in multiple myeloma has been intensively debated. In this study, we evaluated the response to treatment with interferon-α in relation to genetic variation in genes related to inflammation.

Design and Methods

In a retrospective study of 296 patients with multiple myelom undergoing high-dose therapy between 1994 and 2004, 146 patients were treated with interferon-α as maintenance therapy. We tested the polymorphisms IL1B T-31C, IL6 G-174C, NFKB1-94ins/delATTG, CD3EAP G-21A and PPP1R13L IVS1 A4364G for associations with time to treatment failure and overall survival with and without interferon-α treatment.

Results

The wild type ins-allele of polymorphism NFKB1-94 ins/delATTG was, by multivariate Cox analysis, associated with longer time to treatment failure (p=0.01) and overall survival (p=0.0084) when tested between treatment arms and in the subgroup of patients treated with interferon-α the wild type ins-allele was associated with longer overall survival (p=0.002). In the absence of interferon-α treatment, there was no association between the polymorphisms and treatment outcome, except for patients homozygous for the wild type G allele of IL6 G-174C who survived longer (p= 0.0074) than variant allele carriers. There was no association between the polymorphisms IL1B T-31C, CD3EAP G-21A and PPP1R13L IVS1 A4364G and treatment outcome for interferon-α.

Conclusions

Patients who are homozygous carriers of the wild type ins-allele of the NFKB1 -94ins/delATTG polymorphism may benefit from treatment with interferon-α, in contrast to patients carrying the variant allele. This result may indicate that the effect of interferon-α treatment is dependent on the availability of nuclear factor-κB and the polymorphism in NFKB1 may, therefore, be a good prognostic marker for multiple myeloma patients on maintenance treatment with interferon-α after high-dose therapy. A prospective study of interferon-α treatment in relation to NFKB1 -94ins/delATTG is highly warranted.     

Islet cell autoantibodies in patients younger than 20 years of age with recently diagnosed diabetes in Northwest of Iran

The presence or absence of islet cell autoantibodies is one of the most direct ways to distinguish between type 1 and 2 diabetic patients. The objective of the present study was to assess the prevalence of β-cell autoantibodies such as glutamic acid decarboxylase-65 antibodies (GADAs) and islet cell antibodies (ICA) among patients younger than 20 years of age with recently diagnosed diabetes in northwest of Iran. From 2006 to 2008, 163 patients were enrolled in this study. They were clinically classified into two groups: 136 with type 1 diabetes (T1D) and 27 with type 2 diabetes (T2D). Serum levels of GADAs, ICA and C-peptide were determined with enzyme linked immunosorbent assay (ELISA) kits. Fasting blood glucose and HbA1c levels were also determined. Chi-square test, independent t test and one-way analysis of variance were used for data analysis. The prevalence of GADAs in T1D patients was 33.1%, slightly lower than that of ICA 35.3%. Forty-eight patients (35.3%) with T1D were positive for ICA compared to only one (3.7%) in T2D patients. The overall occurrence of any autoantibody in T1D patients (60.3%) was significantly higher than that of T2D patients (18.5%) (P?<?0.001). There was a statistically different association with family history of diabetes among the autoantibody positive versus autoantibody negative patients with T1D (P?<?0.01). Our results confirmed the presence of GADAs and ICA in T1D patients in Iran, though roughly at a lower prevalence than that reported for Caucasian T1D patients, but very similar to other non-Caucasian ethnic populations.     

Is there a role for "watch and wait" in patients with mantle cell lymphoma?

Up to one third of patients with mantle cell lymphoma (MCL) may be observed for a period of months to years before developing indications for therapy. Importantly, observational studies suggest that this approach has no apparent negative impact on their overall survival. Although there is broad agreement on which patients require early therapy, identification of patients with less aggressive disease can be challenging. Clinical tools such as the Mantle Cell International Prognostic Index (MIPI) and Ki67 are effective at predicting survival but may not always correspond with indications for treatment. Research tools such as the proliferative signature are attractive but have yet to be evaluated in this context. Physicians, therefore, must make decisions regarding therapy based on the best available evidence. In the absence of evidence that treatment necessarily influences long-term survival, it may be reasonable to observe selected patients for a period of time prior to making definitive treatment-related decisions. Collaborative efforts are required to better understand the pathophysiology of the disease and potentially identify patients amenable to "watch and wait." Similarly, patients with less aggressive MCL may be an ideal group in which to evaluate novel treatment approaches.     

Interleukin-2 and granulocyte–macrophage–colony-stimulating factor immunomodulation with high-dose chemotherapy and autologous hematopoietic stem cell transplantation for patients with metastatic breast cancer

Immunomodulation with cytokines was used to improve the result of high-dose chemotherapy (HDC)/autologous hematopoietic stem cell transplantation (AHST). We examined the use of IL-2 and growth factors for mobilization, ex vivo activation of peripheral blood stem cell (PBSC) and maintenance therapy after HDC/AHST in metastatic breast cancer. Eligible patients with metastatic breast cancer for HDC/AHST were assigned to 1 of 3 protocols for PBSC mobilization: G-CSF (group 1); IL-2 + G-CSF (group 2); or IL-2 + G-CSF + GM–CSF (group 3). HDC with cyclophosphamide, carmustine and thiotepa was given from day ?7 to ?5. PBSCs were treated ex vivo with IL-2 for 24 h and reinfused on day 0. Maintenance therapy included low-dose IL-2, followed by 2 courses of intermediate-dose IL-2. GM–CSF was given from day 1 until neutrophil recovery. Thirty-four patients (10 in group 1, 14 in group 2, and 10 in group 3) were included. Comparable numbers of CD34⁺ cells were collected from all 3 groups; incremental increases of CD3⁺ cells were collected from groups 1 to 2 and to 3 (p = 0.03). Major adverse effects from IL-2 were fever, hypotension and fatigue; no treatment-related mortality was seen. At a median follow-up of 790.5 days (range 150–2,722 days), median progression-free survival was 434 days and median overall survival was 1,432 days. Estimated 3-year progression-free and overall survival rates were 31 and 57%. Our study suggested that the use of IL-2 and growth factors immunomodulation with HDC/AHST was feasible with comparable survival rates.     

Effect of time to infusion of autologous stem cells (24 vs. 48 h) after high-dose melphalan in patients with multiple myeloma

High‐dose melphalan (HD‐Mel) is considered the current standard of care among the preparative regimens used in autologous peripheral blood stem cell transplantation (SCT) for multiple myeloma (MM), but optimal time and schedule of administration is not defined. We retrospectively analyzed outcomes and toxicities of HD‐Mel administered on day ‐2 vs. day ‐1 before autologous stem cells infusion. A total of 138 consecutive MM patients treated at Penn State Hershey Cancer Institute between 2007 and 2010 were included in this study. No difference in time to hematopoietic recovery, common SCT‐related toxicities, and clinical outcomes was seen between patients who received HD‐Mel on day ‐2 (group A, n = 47), and those who received it on day ‐1 (group B, n = 91). Prompt and full hematopoietic recovery occurred even when stem cells were infused between 8 and 24 h after completion of chemotherapy. In the absence of prospective and randomized data, we conclude that a single I.V. infusion of HD‐Mel on day ‐1 is a safe and effective practice, and the so‐called ‘day of rest’ before the transplant appears not to be necessary.     

Phase II study of Rituximab combined with THP-COP as first-line therapy for patients younger than 70 years with diffuse large B cell lymphoma

Introduction

We previously described the effectiveness of the THP-COP regimen comprising cyclophosphamide, pirarubicin (tetrahydropyranyl adriamycin; THP), vincristine and prednisolone in patients with diffuse large B-cell lymphoma (DLBCL). The anthracycline drug THP was apparently less cardiotoxic than doxorubicin. However, that study was completed before rituximab was introduced into clinical practice. We conducted a phase II study to determine the effectiveness of a regimen incorporating rituximab (R-THP-COP) against DLBCL.

Patients

Six to 8 courses of the regimen were administered every 2 weeks in 48 patients who were younger than 70 years.

Results

The complete remission rate was 92%, the 3-year overall survival rate was 83% and 3-year progression free survival rate was 74%. No deaths were associated with the treatment regimen.

Conclusion

We conclude that R-THP-COP regimen is very effective against DLBCL. The results of our study urge randomized trials of R-CHOP and R-THP-COP among patients with CD20+ DLBCL.     

Do all patients with primary refractory/first relapse of HL need autologous stem cell transplant?

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