[Show abstract][Hide abstract] ABSTRACT: Although advanced stage aggressive non-Hodgkin's lymphomas and Hodgkin's 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.
[Show abstract][Hide abstract] ABSTRACT: Interferon α (IFNα) prolongs survival of CML patients achieving CCyR and potentially synergizes with TKIs. We report on the molecular status and long term outcome of 121 patients who were treated in Italy between 1986 and 2000 with IFNα based therapy and who obtained CCyR. After a median follow up of 16.5 years, 74 (61%) patients were switched to standard imatinib: 48 (65%) lost the CCyR on IFNα, and 36 (75%) are alive and in CCyR; 26 (35%) were switched to imatinib when they were still in CCyR on IFNα, and all 26 are alive and in CCyR. Forty-seven patients (39%) were never switched to imatinib: 24 (51%) continued and 23 (49%) discontinued IFNα, respectively, and 39/47 (83%) are alive and in CCyR. At last follow-up, the BCR-ABL transcripts level was available in 96/101 living patients (95%) The BCR-ABL:ABL ratio was between 0.1 and 0.01% (MR(3.0) ) in 17%, and less than 0.01% (MR(4.0) ) in 81% of patients. No patient was completely molecular negative (MR(4.5) or MR(5.0) ). The OS at 10 and 20 years is 92% and 84%, respectively. This study confirms that CCyR achieved with IFNα and maintained with or without imatinib or any other therapy significantly correlates with long term survival in CML patients who mostly have MR(4.0) . Complete molecular response (MR(4.5) or MR(5.0) ) seems to be unecessary for such a long survival. This study further supports development of studies testing the clinical effect of the combinations of TKIs with IFNα.
Full-text · Article · Oct 2013 · American Journal of Hematology
[Show abstract][Hide abstract] ABSTRACT: 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.
No preview · Article · Aug 2013 · Expert Review of Hematology
[Show abstract][Hide abstract] ABSTRACT: A 9-year-old female received an allogeneic stem cell transplant (SCT) from an ABO-incompatible HLA-matched sibling for β-thalassemia major, without achieving a complete donor chimerism. Subsequently, the patient received five donor lymphocyte infusions, without increasing donor chimerism, and autologous SCT. Due to the persistent bone marrow aplasia, the patient received a second allogeneic SCT from the same donor without obtaining any engrafment. After the double transplant failure, we performed an unrelated transplant from a full-matched umbilical cord blood (UCBT) without administering any neither conditioning regimen nor GVHD prophylaxis. Forty days after UCBT, trilinear engraftment was documented. Surprisingly, the hematopoietic reconstitution was related to the re-expansion of the autologous (beta-thalassemic) hematopoietic stem cell, as documented by chimerism studies. At present, 30 months after UCBT, there is stable hematopoietic autologous reconstitution. This is the first description of the restoration of autologous hematopoiesis obtained with UCBT in a thalassemia-major patient after a double transplant failure.
Full-text · Article · Apr 2013 · Mediterranean Journal of Hematology and Infectious Diseases
[Show abstract][Hide abstract] ABSTRACT: Aim:
To address the incidence and the prognostic role of a very early standard complete cytogenetic response (CCyR) or all Ph- metaphases (MET-, when <20 cells were evaluable).
We revised 182 chronic phase chronic myelogenous leukemia patients treated with frontline imatinib (IM) at two institutions from June 2002 to June 2011.
After 3 months of treatment, 138 patients (75.8%) achieved CCyR/MET- while 44 patients (24.2%) still presented Ph+ metaphases (MET+) (<33%, 24 patients; ≥33%, 20 patients). On univariate analysis, palpable spleen enlargement (p < 0.001), WBC count >100.0 × 10(9)/l at onset (p < 0.001), and male gender (p = 0.019) had a negative impact on achievement of CCyR/MET- at 3 months. Among patients with CCyR/MET- after 3 months, there were 15 failures (10.8%) compared to 21 (47.7%) among patients with MET+ (p < 0.001). The 5-year overall survival was 97.0% in patients CCyR/MET- at 3 months and 91.8% in patients MET+ at 3 months (p = 0.277); the 5-year progression-free survival was 88.2% in patients CCyR/MET- at 3 months and 48.4% in patients MET+ at 3 months (p < 0.001).
The achievement of CCyR/MET- at 3 months seems to have prognostic relevance and could be a very early and useful indicator of an excellent response to IM beyond European LeukemiaNet guidelines.
Full-text · Article · Nov 2012 · Acta Haematologica
[Show abstract][Hide abstract] ABSTRACT: The role of high-dose therapy (HDT) followed by autologous stem cell transplantation (ASCT) in the treatment armamentarium of aggressive B- and T-cell non-Hodgkin lymphoma (NHL) is still a matter of debate. In the pre-Rituximab era, the PARMA study demonstrated the superiority of HDT/ASCT over conventional salvage chemotherapy in chemosensitive, relapsed patients. Subsequently, HDT/ASCT has become a standard approach for relapsed NHL. With the advent of Rituximab in the landscape of NHL, transplantation as part of first-line therapy has been challenged. However, no benefit in terms of disease-free or overall survival of HDT/ASCT over standard therapy was shown when Rituximab was added to both arms. Moreover, the superiority of HDT/ASCT over conventional salvage therapy in patients relapsing from first-line therapy including Rituximab was not confirmed. From these disappointing results, novel strategies, which can enhance the anti-lymphoma effect, at the same time reducing toxicity have been developed, with the aim of improving the outcome of HDT/ASCT in aggressive NHL. In T-cell lymphoma, few publications demonstrated that consolidation of complete remission with HDT/ASCT is safe and feasible. However, up to one-third of patients may never receive transplant, mostly due to progressive disease, and relapse still remains a major concern even after transplant.
Full-text · Article · Nov 2012 · Mediterranean Journal of Hematology and Infectious Diseases
[Show abstract][Hide abstract] ABSTRACT: Introduction. Cytomegalovirus (CMV) reactivation is a frequent complications of allogeneic stem cell transplantation. However, informations regarding the incidence and the clinical impact of CMV reactivation after autologous stem cell transplant (ASCT) are limited. Methods. Ninety-two patients consecutively submitted to ASCT for B-cell malignancies were monitored for CMV reactivation. Twenty-nine patients had multiple myeloma, 63 a lymphoproliferative disease (HD, NHL, CLL). Twenty-seven patients received ASCT for a resistant disease, whereas 65 for a newly diagnosed disease. Thirty-six patients received anti-CD-20 antibody as a part of the frontline therapy before ASCT. The conditioning regimen was BEAM for 47/92 patients, high-dose Melphalan for 28/92 patients and BAVC or Busulphan/Endoxan for the remaining 17 patients. Sixty-six patients received peripheral blood stem cells rescue after high dose therapy, whereas 26 got bone marrow stem cells. CMV reactivations were monitored twice weekly with the polymerase chain reaction (PCR) assay in all patients, starting after the engraftment. Results. Twenty-five out of 92 patients (27%) presented a CMV reactivation. The great majority of patients (17/25, 68%) reactivated CMV after 30 or more days from transplant. Moreover, 15/25 patients (60%) presenting a CMV reactivation had received prior Rituximab. Ten out of 25 patients (40%) presented symptoms such as fever, vomiting, arthralgia or profound asthenia at reactivation. Moreover, CMV reactivation was associated with moderate to severe neutropenia in 8/25 patients. All patients reactivating CMV were treated with intravenous (iv) ganciclovir given 7.5 mg/kg once daily for a median of 20 days (range: 6-40). Discontinuation of antiviral therapy required at least two consecutively negative PCRs performed at least 3 days apart each other. All patients experienced a negativization of CMV-specific PCR after a median of 12 days of therapy (range: 9-34). None of the patient developed CMV disease. Moreover, no late infections or other side effects were observed during the long-term follow-up period. Conclusion. In conclusion, our experience clearly demonstrates that a significant proportion of patients submitted to ASCT develop a CMV reactivation after transplant, frequently symptomatic, requiring antiviral therapy. We underline the necessity of a stringent monitoring of CMV reactivation after ASCT, especially for patients receiving therapy with anti-B lymphocytes monoclonal antibodies before transplant.
No preview · Article · Oct 2012 · Giornale Italiano di Farmacia Clinica
[Show abstract][Hide abstract] ABSTRACT: Background / Purpose:
Our aim was to demonstrate the safety and efficacy of dasatinib as second line therapy for unselected patients with CML either resistant or refractory to IM outside clinical trials.Dasatinib (BMS-354825) is a multi-targeted kinase inhibitor of BCR-ABL and SRC with significant activity in patients with CML resistant or intolerant to front-line imatinib (IM). However, the information so far available is to a great extent limited to controlled clinical trials, which usually recruit patients with acceptable performance status, and no major organ dysfunction. It is noteworthy that, although essential for ethical reasons in clinical trials, this fact may somehow determine an overestimation of the clinical benefit of new compounds. Thus, further studies based on non-selected populations are indeed opportune.A total of 124 patients (61 male and 63 females) with CML resistant or intolerant to IM received dasatinib as second line therapy outside clinical trials. 91 patients had a resistant disease, 19 were intolerant to IM and 14 patients were both resistant and intolerant to IM. Median age at switching to dasatinib was 56.5 years (range 21-82). 62/124 patients escalated IM before switching from 400 to 600 mg/day and 26/62 patients received an additional dose escalation from 600 to 800 mg/day. Median time on IM prior to the switch to dasatinib was 36 months (range 2-99), whereas median time on IM after dose escalation was 9 months (range: 1-43). Dasatinib was given at 100 mg once daily in 54/124 patients (43%), at 70 mg twice daily in 43/124 patients (35%) and at 50 mg once daily in the remaining patients (22%). Response (hematologic, cytogenetic and molecular), toxicities according to NCI-CTC, discontinuation/dose reduction of dasatinib, event-free survival (EFS) and overall survival (OS) were evaluated.
With a median follow-up of 12 months, 94% of patients attained a complete hematological response (CHR), whereas 69% and 51% achieved a major (MCyR) or a complete cytogenetic response and 32% attained a major molecular response (MMR). Cumulative EFS and OS at 12 months were 91 and 93% respectively. These data are in line with those of clinical trials, but the population of the present study was not selected. The commonest grade III/IV adverse events were thrombocytopenia and neutropenia, occurring in around half of patients. Only 3% of the patients suffered from a grade III-IV pleural effusion or dyspnea. The achievement of CHR, MCyR, CCyR and MMR significantly influenced EFS (p=0.006; 0.04; 0.008 and 0.003 respectively) and OS (p=0.002; 0.02; 0.004 and 0.001 respectively) both in univariate and in multivariate analysis.Intriguingly, neither the dose nor the duration of prior IM affected the response to dasatinib, neither before switching to dasatinib (p=0.9 and 0.4) nor after it (p=0.4 and 0.7). Moreover, dose escalation to IM 600 or 800 mg/day did not influence negatively the subsequent response to dasatinib (p=0.8). In addition, we did not observe any difference in the response rate (CHR, MCyR, CCyR, MMR) between patients who received prior IM for more than 3 years with respect to those patients who received it for less than 3 years (p=0.9). Regarding dasatinib therapy, we observed a statistically significant better outcome in term of both DFS and OS for those patients receiving lower doses continuously without interruption (p=0.04 and 0.04) with respect to patients who received higher doses but forced to stop the treatment due to grade III-IV toxicity. This observation clearly indicate the necessity of administer dasatinib continuously to patients in order to override possible mechanisms of resistance due to the reduction of the plasma level of the drug.We confirm the safety and efficacy of dasatinib as second line therapy for unselected patients with CML either resistant or refractory to IM even outside clinical trials. Neither the dose nor the duration of IM affects the response to dasatinib. Patients receiving continuous dasatinib, even at low doses, perform better. In conclusion, these findings show an increase possibility of cure for unselected patients resistant or intolerant to IM submitted to second line therapy with dasatinib in everyday clinical practice.
[Show abstract][Hide abstract] ABSTRACT: 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 > or =2. Fifteen out of 20 patients (75%) had an International Prognostic Index (IPI) score > or =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.
[Show abstract][Hide abstract] ABSTRACT: 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.
No preview · Article · Jan 2007 · Leukemia and Lymphoma
[Show abstract][Hide abstract] ABSTRACT: Combined high-dose Interferon-alpha and psoralen plus ultraviolet A irradiation (PUVA) have been reported to be effective in the treatment of early mycosis fungoides (MF); however, our study is the first controlled prospective study in the literature exploring the activity and tolerability of the combination with low dosages and evaluating further clinical outcome of early-MF patients.
We carried out a multicentric prospective Phase II clinical study on 89 patients with early-stage IA to IIA MF treated for 14 months with low-dose IFN-alpha2b (6-18 MU/wk) and PUVA. Treatment success was analysed in terms of freedom from treatment failure.
Complete remission (CR) was achieved in 84% and an overall response rate in 98% of cases: six-month CR was associated with a non-confluent skin infiltrate at histology (P = 0.044) and 14-month CR with high epidermal CD1a+ dendritic-cell density (P = 0.030). The combination protocol was successfully tolerated and the most common reason of 'failure' was related to relapse and not to toxicity. Sustained remissions were achieved in 20% of patients. High CD8+ lymphoid T-cell density was associated with a lower relapse rate (P = 0.002). We think that our combination therapy can be considered an alternative approach compared with other modalities. Good immunological host surveillance in the skin lesions seems to be an optimal basis for the therapeutic success.
No preview · Article · Sep 2005 · European Journal Of Haematology
[Show abstract][Hide abstract] ABSTRACT: 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/microL. The median number of harvested CD34+ cells was 8.1 x 10(6)/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.
No preview · Article · May 2005 · European Journal Of Haematology
[Show abstract][Hide abstract] ABSTRACT: The early stages of mycosis fungoides (MF) can be treated but not cured by photochemotherapy (PUVA) alone; some recent studies of the effect of a combination of human interferon-alpha (IFN(alpha)) and PUVA reported a high degree of response. The aim of our study was to evaluate the activity of a low dose of IFN-alpha2b combined with PUVA.
Twenty-five patients were included: 16 men and 9 women aged between 23-80 years; 19 patients ahd stage I and 6 stage II disease. In the induction phase, the dose of IFNalpha was gradually raised over 6-8 weeks to the target dose of 18 MU/week; in the maintenance phase, the combination with PUVA allowed IFNalpha to be reduced to a maximum dose of 6 MU/week; in this way the cumulative administration of IFNalpha and PUVA was considerably lower than in similar combination protocols. Treatment success was analyzed in terms of freedom from treatment failure (FFTF).
After the induction phase 9/25 patients (36%) achieved complete remission (CR) and 15/25 (56%) achieved partial remission (PR). One to five months from the beginning of the maintenance phase, a CR was recorded in 19/25 patients (76%) and a PR in 5/25 patients (20%) accounting for an overall response rate of 96%. The median of FFTF was not reached; probability of FFTF was 82% at 12 months and 62% at 24 months. Disease free survival projected to 48 months was 75%.
Even with low doses of IFNalpha plus PUVA it is possible to achieve excellent clinical responses,many of which are long-lasting, in patients with early MF.
[Show abstract][Hide abstract] ABSTRACT: Granulocyte colony stimulating factors (G-CSF) has a wide spectrum of action: it stimulates proliferation and differentiation of granulocyte-macrophage progenitors, it promotes the chemotactic activity of monocytes and granulocytes and it develops the antibody-dependent cytotoxicity of neutrophils. In vivo G-CSF induces leucocytosis and it hastens the granulocyte recovery after chemio-radiotherapy. So it has been used in many pathologies: aplastic anaemia, AIDS in treatment with antiviral drugs, myelodysplastic syndromes, acute leukemias and solid tumors. If G-CSF is administered after chemotherapy, both in acute leukemias and in solid tumors, it reduces the duration of neutropenia and the number of febrile episodes so that it is possible to give the whole therapy at the planned dosage with no delay. However G-CSF does not modify the incidence of complete remissions and the overall survival. G-CSF allowed the increase of dose-intensity in chemoresistent neoplasms even if this therapy is always complicated by a heavy extrahaematological toxicity. Moreover G-CSF shortens the total duration of neutropenia after autologous or allogenic bone marrow and peripheral stem cell transplantation even if the appearance of the first neutrophil is not accelerated.
No preview · Article · Jan 1996 · Recenti progressi in medicina
[Show abstract][Hide abstract] ABSTRACT: Primary myelofibrosis is a complex disorder characterized by bone marrow fibrosis with no apparent cause. It is known in literature under a wide number of terms, reflecting the variety of clinical features and the different pathogenetic hypotheses. In most cases it is plain that marrow fibrosis is secondary to a clonal myeloproliferative disorder and, in particular, to the presence of abnormal megakaryocytes secreting (MKDGF/PDGF); but probably some other growth factors synthesized by megakaryocytes and contained in platelet alpha-granules are involved. The molecular event that determines the advantage of the clonal growth is, at present, unknown, and the pathogenetic importance of some chromosome anomalies is still under discussion. Over the last years, besides megakaryocyte dysplasia, several fibrogenetic mechanisms such as a bone marrow immune damage have been taken into consideration. Studies on prognostic factors regarding the main clinical, hematological and histological parameters have given conflicting results, because of low incidence of the disease, different criteria used for the diagnosis, and different terms of the clinic presentation of the pathology. Although a great deal of progress has been made in terms of pathogenetic mechanisms, a lot of questions must be still definitively settled, further in depth studies still have to go into many matters.
No preview · Article · · Recenti progressi in medicina