Barbara Guiducci

R-COMP 21 for frail elderly patients with aggressive B-cell non-Hodgkin lymphoma: A pilot study

We evaluated the toxicity and efficacy of nonpegylated liposomal doxorubicin (Myocet®) when substituted for conventional doxorubicin in the CHOP-21 regimen in the treatment of frail elderly patients with aggressive non-Hodgkin lymphoma. Twenty frail patients (median age, 73 years), as defined by Balducci et al., with diffuse large B cell or grade IIIb follicular lymphoma, either at diagnosis (15 patients) or relapsed (five patients), were prospectively enrolled. Nine out of 20 (45%) had a World Health Organisation (WHO) performance status ≥2. Fifteen out of 20 patients (75%) had an International Prognostic Index (IPI) score ≥3. Thirteen out of 20 (65%) evaluable patients obtained a complete response. Five additional patients (25%) achieved a partial response. With a median follow-up of 24 months (range 18–27), 15/18 responding patients (83%) are alive and disease free, as well as 3/18 are alive with active disease. Toxicity was mainly hematological with grade 3/4 neutropenia in 26% of cycles and febrile neutropenia in 5%. However, 3/20 patients presented a grade III–IV WHO toxicity (one fatal pulmonary embolism, one congestive, and one ischemic heart failure) while receiving R-COMP chemotherapy. In conclusion, R-COMP-21 is an effective regimen with promising response rates for frail and elderly patients with aggressive non-Hodgkin lymphoma.

Tailored therapy in an unselected population of 91 elderly patients with DLBCL prospectively evaluated using a simplified CGA.

BACKGROUND Elderly patients with diffuse large B-cell lymphoma (DLBCL) are a heterogeneous population; clinical trials have evaluated a minority of these patients. PATIENTS AND METHODS Ninety-one elderly patients with DLBCL received tailored treatment based on a comprehensive geriatric assessment (CGA). Three groups were identified: I, fit patients; II, patients with comorbidities; III, frail patients. Group I received 21-day cycles of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP-21), group II received R-CHOP-21 with liposomal doxorubicin, and group III received 21-day cycles of reduced-dose CHOP. Fifty-four patients (59%) were allocated to group I, 22 (25%) were allocated to group II, and 15 (16%) were allocated to group III. RESULTS The complete response (CR) rates were 81.5% in group I, 64% in group II, and 60% in group III. With a median follow-up of 57 months, 42 patients are alive, with 41 in continuous CR: 31 patients (57%) in group I, seven patients (32%) in group II, and four patients (20%) in group III. The 5-year overall survival, event-free survival, and disease-free survival rates in all patients were 46%, 31%, and 41%, respectively. Multivariate analysis selected group I assignment as the main significant prognostic factor for outcome. CONCLUSIONS This approach in an unselected population of elderly DLBCL patients shows that treatment tailored according to a CGA allows the evaluation of elderly patients who are currently excluded from clinical trials.

Cyclophosphamide, pegylated liposomal doxorubicin, vincristine and prednisone (CDOP) plus rituximab is effective and well tolerated in poor performance status elderly patients with non-Hodgkin's lymphoma

Lymphomas in elderly patients require special attention, not only for possible important co-morbidities and poor performance status, but also for diminished organ functions and altered drug metabolism, which modify the pharmacokinetics of the treatment [1]. Thus, first-line elderly non-Hodgkin’s lymphoma (NHL) patients are frequently treated with a consequent dose reduction [2,3]. Similarly, the treatment outcome of salvage therapy for relapsed/ refractory NHL patients is limited by multidrug resistance, low performance status and the high toxicity of secondand third-line regimens. Anthracycline-based regimens are extremely effective in NHL; the main disadvantage is cardiotoxicity. Pegylated liposomal doxorubicin has been shown to determine lower toxicity if compared with conventional doxorubicin, while having similar efficacy in patients with Kaposi’s sarcoma and solid tumors. Due to the prolonged half-life (nearly 43 h), it offers the opportunity of obtaining prolonged exposure of tumor cells to active concentrations, with possible effects on the disease. A recent study concluded that an improvement in the survival of elderly patients with lymphoma is related to an optimized toxicity chemotherapy schedule [4,5]. In addition, cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) plus rituximab has been demonstrated to be superior to CHOP alone in elderly patients with diffuse large cell lymphoma [6,7]. We thus tested the safety and efficacy of a regimen [cyclophosphamide, pegylated liposomal doxorubicin, vincristine and prednisone (CDOP) plus rituximab] using a pegylated liposomal doxorubicin instead of conventional doxorubicin, in order to reduce the toxic profile and preserve the dose intensity, administered as follows: day 1, cyclophosphamide 750 mg/m, pegylated liposomal doxorubicin (Caelyx, Schering Plough S.A., Italy) 40 mg/m, vincristine 1.4 mg/m, prednisone 100 mg p.o. days 1 – 5, rituximab 375 mg/ m on day 15 of every cycle; granulocyte colonystimulating factor (G-CSF) from day 10 to day 14. Therapy was repeated every 21 days for 6 cycles. Complete and partial remission were assessed as the overall response. Toxicity was evaluated according to the WHO criteria. Thirteen patients were treated (Table I); 12 (92%) completed the 6 courses and were assessable for response (Table II). A dose reduction (25%) was carried out in 2 cases (1 frail, 1 relapsed-refractory), due to their extremely altered clinical condition. Seven patients (53%) obtained complete remission, 5 (31%) partial remission, for an overall response rate of 84%. No major toxicity (WHO grade III/IV) occurred. Only 1 patient delayed therapy for grade II hematological toxicity. After a median follow-up of 18 months (range 8 – 22 months), 7 patients are in continuous complete remission (53%), 3 (23%) in partial remission, 1 in stable disease, whereas only 2 patients progressed. In our opinion, one of the reasons for the high overall response rate (84%) and of the maintenance of the response, even in this category of very fragile patients, is the respect of the doses, as well as of the

High-dose therapy followed by stem cell transplantation in Hodgkin’s lymphoma: past and future

Hodgkin’s lymphoma (HL) has been a fascinating challenge for physicians and investigators since its recognition during the 19th century. However, many questions still remain unanswered. One issue regards high-dose therapy followed by autologous stem cell transplantation (ASCT), which has yet to find its place among several guidelines. Other topics are still controversial with respect to transplantation for HL, including its role for newly diagnosed patients with advanced stage disease, the optimal timing of transplantation, the best conditioning regimen and the role of allogeneic/haploidentical SCT. Moreover, the potential use of localized radiotherapy or immunologic methods to decrease post-transplant recurrence, the role of novel agents such as brentuximab vedotin and their positioning in the treatment algorithm of resistant/relapsed HL patients, either before transplant to boost salvage therapy or after transplant as consolidation/maintenance, are burning questions without an answer. In this review, the authors try to give an answer to some of these dilemmas.

An observational study of once weekly intravenous ganciclovir as CMV prophylaxis in heavily pre-treated chronic lymphocytic leukemia patients receiving subcutaneous alemtuzumab

Fifteen consecutive resistant/relapsed chronic lymphocytic leukemia (CLL) patients (median age: 65 years) received alemtuzumab for 16 consecutive weeks. All patients had negative CMV anti genemia at baseline. Five patients received oral acyclovir 800 mg twice a day for CMV prophylaxis and 10 patients got intravenous (iv) ganciclovir 7.5 mg/kg once a week. A total of five CMV reactivations occurred, four in the acyclovir and one in the ganciclovir prophylaxis group. Alemtuzumab was then discontinued and all patients were treated with iv ganciclovir 7.5 mg/kg per day. All patients achieved negative CMV anti genemia after a median of 15 days of therapy. Weekly iv ganciclovir prophylaxis and alemtuzumab treatment were then restarted without any further CMV reactivations. In conclusion, weekly iv ganciclovir appears feasible and effective in preventing CMV reactivation and disease in this setting of high-risk immunocompromised patients, allowing an easier management of a therapy otherwise difficult to be routinely used.

Deferasirox improves hematopoiesis after allogeneic hematopoietic SCT

Iron overload is frequently observed before hematopoietic SCT (HSCT), due to multiple RBC transfusions, and is considered a significant contributor to treatment-related mortality. Little is known of the effects of iron overload on hematopoietic recovery after transplant. In fact, several patients present impaired recovery of hemopoiesis after transplant, with transfusion dependence and/or neutropenia and thrombocytopenia. All the same, the possible effect of iron chelators on the restoration of normal hemopoiesis after transplant is still unknown. Here we report on eight patients with incomplete hematological reconstitution after allogeneic HSCT, heavily transfused before transplant, who were treated after HSCT with deferasirox (Table 1). Patients were selected according to the following inclusion criteria: (1) recipient of allogeneic HSCT; (2) transfused pre-transplant with more than 20 RBC units; (3) incomplete hematological recovery; (4) transfusion dependence; (5) serum ferritin X1800 ng/mL; (6) normal creatinine value; (7) signed informed consent. Before starting deferasirox, all patients were fully engrafted and in CR. All patients received an initial dose of deferasirox 10mg/kg/day, later adjusted according to side effects. Deferasirox was well tolerated; all patients experienced an increase in Hb levels, with a reduction in the frequency of RBC transfusions, followed by transfusion independence (median time: 23 days from the first dose of deferasirox; Figure 1a). In addition, it was promptly (median time: 26 days) associated with hematological improvement, with sustained values and no further platelet support or growth factor administration. Moreover, ferritin values were progressively reduced with deferasirox treatment (Figure 1b). The workup for other etiologies was negative; no concomitant infection was documented (CMV: negative; HHV-6: negative; EBV: negative). No relevant modifications with immunosuppressive or myelosuppressive drugs were made during deferasirox treatment. In our opinion, deferasirox had a direct stimulatory effect on hematopoiesis after allo-SCT. The role of iron overload after HSCT is not completely understood. Recent evidence suggests that increased liver iron concentration (LIC) measured with liver magnetic resonance (R2magnetic resonance imaging) or liver biopsy do not correlate with survival or incidence of complications at 1-year post transplant. However, in the recent past, an association between serum ferritin values before HSCT (used as a surrogate measure of iron overload) and an adverse outcome was shown, leading to the conclusion that hyperferritinemia has a detrimental effect on survival up to 5-year post transplant. Thus, interventions to reduce excessive body iron might be beneficial both before and after HSCT. In the peri-transplant period, BM suppression caused by chemotherapeutics substantially increases toxic nontransferrinbound iron levels, because erythropoiesis is the main route of circulating iron utilization. An attractive explanation for the post

Advancement in high dose therapy and autologous stem cell rescue in lymphoma

Although advanced stage aggressive non-Hodgkins lymphomas and Hodgkins disease are thought to be chemotherapy-responsive cancers, a considerable number of patients either relapse or never attain a remission. High-dose therapy (HDT) followed by autologous stem cell transplantation (ASCT) is often the only possibility of cure for most of these patients. However, many controversial issues still remain with respect to HDT/ASCT for lymphomas, including its role for, the optimal timing of transplantation, the best conditioning regimen and the potential use of localized radiotherapy or immunologic methods to decrease post-transplant recurrence. Recently, mainly due to the unavailability of carmustine, several novel conditioning protocols have been clinically developed, with the aim of improving the overall outcome by enhancing the anti-lymphoma effect and, at the same time, by reducing short and long-term toxicity. Furthermore, the better safety profiles of novel approaches would definitively allow patients aged more than 65-70 years to benefit from this therapeutic option. In this review, we will briefly discuss the most relevant and recent data available regarding HDT/ASCT in lymphomas.

Mini-ICE effectively mobilises peripheral blood stem cells after fludarabine-based regimens in acute myeloid leukaemia

Fludarabine‐based cycles severely impair mobilisation and collection of peripheral blood stem cells (PBSC) in acute myeloid leukaemia (AML). In an effort of reversing this side‐effect, we studied the action on mobilisation and collection of PBSC of a low‐dose regimen: 5‐d Mini‐ICE (oral idarubicin and etoposide; subcutaneous cytosine arabinoside) administered after fludarabine‐based regimens in seven adult AML patients. Leukapheresis were started when the CD34+ cell count was more than 10/μL. The median number of harvested CD34+ cells was 8.1 × 106/kg (range 3.08–15.2). All the patients were successfully submitted to PBSC transplantation. Median times to neutrophil and platelet recovery were rapid with a normal transfusional support. We suggest that the Mini‐ICE programme is feasible, well tolerated and effective in terms of PBSC mobilisation and collection in low‐yield AML patients previously treated with fludarabine. It is well known that a negative effect on stem cell mobilisation and harvest is observed not only after fludarabine administration in AML or low‐grade lymphomas, but also after cycles based on different agents, such as thalidomide in multiple myeloma. This preliminary experience, if confirmed on larger series and/or other haematological malignancies, could open new opportunities to perform autologous PBSC transplantation in heavily pretreated cases, allowing a full source of therapeutic options before the start of the mobilisation process.

PBSC mobilization in patients with autoimmune diseases: what's next

The arrival of modern biological-based therapies improved outcome in many autoimmune diseases (ADs) in recent years. However, a significant proportion of patients still does not respond to these therapies, or develop unacceptable side effects. Autologous hematopoietic stem cell transplantation (AHSCT) has been proposed as a treatment modality, which may arrest the autoimmune disease process and lead to sustained treatment-free remissions. The feasibility and efficacy of AHSCT were recently demonstrated by two randomized controlled trials in ADs (1, 2). As a consequence, the European Group for Blood and Marrow Transplantation (EBMT) Autoimmune Disease Working Party (ADWP) has recommended to consider AHSCT as a therapeutic option ‘at second line or beyond for patients with severe ADs progressing despite standard established and/or approved therapy (level II)’ (3). However, although high-dose therapy (HDT) and AHSCT are used since almost 20 yrs for systemic sclerosis (SSc) and other ADs, only little is known about the mobilization efficiency in these patients. Moreover, several hot questions regarding PBCS mobilization have not been answered, not only in ADs: the optimal mobilization regimen, G-CSF multiple dosing, graft composition, poor mobilization in some patients, number of aphaeresis, and inability to predict optimal mobilization times (4). Finally, patients with SSc may have an impaired capacity of mobilizing hemopoietic stem cells (HSCs) from marrow to peripheral blood, due to the presence of an advanced bone marrow fibrosis and/or a reduced microvascularity in the marrow (5). In this issue of the Journal, Blank and co-workers (6) demonstrated the safety and the efficacy of a low-dose cyclophosphamide regimen followed by multiple G-CSF dosing for the mobilization of HSCs in patients with advanced ADs (SSc, multiple sclerosis, and other ADs). In their retrospective, single-center analysis, they were able to effectively mobilize an adequate number of HSC to proceed to AHSCT in 35 of 35 patients treated with this regimen. No collection failures were observed. No major safety issues, comprising deep vein thrombosis during leukoapheresis procedure(s) and infections due to cyclophosphamide chemotherapy, were reported, indicating the overall safety of the program. Nonetheless, 70% of patients were able to collect ad adequate number of HSC with only one procedure, whereas only two of 35 patients needed more than two procedures to meet the target dose. The authors also compared two different dosages of cyclophosphamide (1 9 2 g/m vs 2 9 2 g/m): no major difference in both efficacy and toxicity was reported. This information should be relevant and further investigated, because the lower is the chemotherapy needed to mobilize HSC, the safer is the mobilizing regimen. In this regard, approximately 60% of the patients were mobilized outpatient, further reducing the costs of the procedure. Notably, the outpatient mobilization was not possible in all patients due to the presence of comorbidities related to ADs that, in any case, did not prevent this patient population from a successful mobilization followed by ASCT. It is important to stress that no correlation was found between CD34cells 9 10/kg body weight and age, modified Rodnan skin score, SSc-disease duration, or previous cyclophosphamide dose in SSc. Thepatientscollected a median number of 8.0 CD34cells 9 10/kg, doubling the threshold considered safe to candidate such patient to HDT and AHSCT. In conclusion, this study provides a rationale for the reduction of the cumulative cyclophosphamide dose prior to HDT and AHSCT in patients with ADs refractory to prior therapies and not eligible for novel agents. Giving the fact that it is still not clear whether patients with ADs may warrant the use of cyclophosphamide in the mobilization regimen to suppress inflammation and halt progression, a reduction in the dose of cyclophosphamide surely reduces the number of days with leucopenia and the total days of G-CSF administration. This should be relevant, because G-CSF is quite toxic in patients with systemic ADs, and therefore, its use should be limited to the strict necessary. In this regard, the better understanding of the mechanisms that lead to the fibrosis of the skin and internal organs, and of the dysfunctional interaction between endothelial cells and mesenchymal stem cells are warranted to hypothesize a possible mobilization regimen without the use of chemotherapy, even at low doses. The effects of other molecules, namely chemokines and small chemoattractans, that exhibited advancement, either quantitative or qualitative, to HSC mobilization in patients with hematological diseases, have yet to be studied in ADs. In vitro studies of the biological Correspondence Alessandro Isidori, MD, PhD, Hematology and

High-dose Benda-EAM versus BEAM in patients with relapsed/refractory classical Hodgkin lymphoma undergoing autologous stem cell transplantation

In patients with relapsed or refractory (R/R) classical Hodgkin lymphoma (HL), high-dose chemotherapy (standard regimens include CBV, BEAC, and BEAM) with subsequent autologous stem cell transplantation (ASCT) remains the standard of care [1]. High-dose carmustine, etoposide, cytarabine, and melphalan (BEAM) has been used for at least two decades, demonstrating a 5-year overall survival (OS) of ~55% [2]. However, there are concerns about the increasing cost, reduced availability, and high toxicity profile of carmustine, particularly second malignancies and interstitial pneumonitis [3]. These concerns highlight the need for an alternate agent or regimen. Visani et al. reported a phase 1–2 study investigating outcomes using bendamustine in place of carmustine together with the other components of BEAM (BendaEAM) in 43 patients [4]. Updated follow-up at 41 months showed that 72% of patients had no evidence of recurrent HL after high-dose Benda-EAM and ASCT [5]. In the present study, we conducted a matched analysis comparing the characteristics, clinical outcomes and toxicities between patients with R/R HL treated with high-dose Benda-EAM or BEAM conditioning regimens followed by ASCT. A total of 26 consecutive patients treated outside of clinical trials with Benda-EAM and ASCT at the Hematology and Stem Cell Transplant Center, AORMN in Pesaro, Italy were identified using the PROMISE database of the European Bone Marrow Transplantation Registry. In British Columbia (BC), Canada, the BC Cancer Centre for Lymphoid Cancer and the Leukemia/Bone Marrow Transplant Program of BC databases were used to identify 82 consecutive patients treated with BEAM and ASCT. Both regimens were administered as previously described [2, 4], although the dose of bendamustine was reduced in 8 Benda-EAM patients (160mg/m (n= 4), 180mg/m (n= 4)) due to age/comorbidities. All patients in BC received BEAM at full doses. During the study period, Benda-EAM was not available in BC. Management of HL at diagnosis and relapse/progression, including choice of chemotherapy, supportive care, response assessment, and follow-up was delivered according to physician discretion and institutional guidelines. In Pesaro, the policy was to administer a greater number of salvage regimens in order to obtain at least PR prior to proceeding with ASCT. In BC, provincial guidelines recommended ASCT after failure of primary therapy even with no response to secondary chemotherapy regimens. Benda-EAM patients (n= 26) were matched 1:2 to BEAM patients (n= 52) on the basis of two predetermined variables [1]: response to first-line therapy (primary These authors contributed equally: Erica S. Tsang and Diego Villa