Direct determination of chronic myeloid leukemia prevalence in Lombardy-Italy: Global implications.

Lombardy represents the largest region of Italy by population, with almost 10 million residents, a dimension similar to a medium size country like Sweden or Belgium. The CML subcommittee of the Lombardy Hematology Network (REL-CML) conducted a study at the beginning of 2023. Prevalence was calculated by direct input from the 21 centers participating in REL-CML. Tyrosine Kinase Inhibitors (TKI) prescription records collected from the ARIA regional registry were used to estimate the number of CML patients followed in smaller centers not participating in REL-CML. A total of 2285 patients were registered, representing a prevalence of 0.23 ‰. These data were compared to a similar census conducted in 2005, at the beginning of the TKI era, where a prevalence of 0.029‰ was calculated. This indicates that an almost 10 times increase took place during this period of time. Imatinib represents the most frequently prescribed first-line TKI; its use in 2022 still represented 75% of total first line prescriptions. An increased concentration of the care of CML patients in specialized REL centers with a decreased dispersion of patients in small centers was also evident over this 18 year period of time. Nineteen % of patients discontinued treatment, highlighting persisting logistical and biological challenges; one some recommendations on CML management are included to this aim.

Hematopoietic stem cell transplantation activity worldwide in 2012 and a SWOT analysis of the Worldwide Network for Blood and Marrow Transplantation Group including the global survey.

Data on 68 146 hematopoietic stem cell transplants (HSCTs) (53% autologous and 47% allogeneic) gathered by 1566 teams from 77 countries and reported through their regional transplant organizations were analyzed by main indication, donor type and stem cell source for the year 2012. With transplant rates ranging from 0.1 to 1001 per 10 million inhabitants, more HSCTs were registered from unrelated 16 433 donors than related 15 493 donors. Grafts were collected from peripheral blood (66%), bone marrow (24%; mainly non-malignant disorders) and cord blood (10%). Compared with 2006, an increase of 46% total (57% allogeneic and 38% autologous) was observed. Growth was due to an increase in reporting teams (18%) and median transplant activity/team (from 38 to 48 HSCTs/team). An increase of 167% was noted in mismatched/haploidentical family HSCT. A Strengths, Weaknesses, Opportunities, Threats (SWOT) analysis revealed the global perspective of WBMT to be its major strength and identified potential to be the key professional body for patients and authorities. The limited data collection remains its major weakness and threat. In conclusion, global HSCT grows over the years without plateauing (allogeneic>autologous) and at different rates in the four World Health Organization regions. Major increases were observed in allogeneic, haploidentical HSCT and, to a lesser extent, in cord blood transplantation.

Bortezomib-based induction for transplant ineligible AL amyloidosis and feasibility of later transplantation.

Recent studies support the use of bortezomib-based therapies in light chain amyloidosis (AL). We performed a retrospective analysis of the safety, efficacy and long-term survival (median follow-up 3 years) after bortezomib-based treatment in 28 consecutive patients with de novo AL deemed ineligible at initial presentation. The first 14 patients received bortezomib and dexamethasone (VD), and the second 14 patients received cyclophosphamide, bortezomib and dexamethasone (CVD; CyBorD). Both regimens were well tolerated with no treatment-related mortality. The overall hematological response (HR) rate was 93% in both the groups. Median time to response was shorter in the CVD group (39 days vs 96 days in the VD group; P=0.002). Hematological and organ responses induced with bortezomib-based therapy enabled 8 (33%) of initially transplant ineligible patients to undergo autologous hematopoietic stem cell transplantation (AHCT), including 4 patients with cardiac stage III or IV. Seven of the eight patients (88%) who underwent subsequent AHCT achieved sustained HR at a median of 33 months posttransplant. These data suggest that bortezomib-based induction followed by AHCT is a viable therapeutic strategy for transplant-ineligible AL. Larger, multicenter prospective trials are necessary to confirm our findings.

Primary graft failure after myeloablative allogeneic hematopoietic cell transplantation for hematologic malignancies.

Clinical outcomes after primary graft failure (PGF) remain poor. Here we present a large retrospective analysis (n=23,272) which investigates means to prevent PGF and early detection of patients at high risk. In patients with hematologic malignancies, who underwent their first myeloablative allogeneic hematopoietic cell transplantation, PGF was reported in 1278 (5.5%), and there was a marked difference in PGFs using peripheral blood stem cell compared with bone marrow grafts (2.5 vs 7.3%; P<0.001). A fourfold increase of PGF was observed in myeloproliferative disorders compared with acute leukemia (P<0.001). Other risk factors for PGF included recipient age <30, HLA mismatch, male recipients of female donor grafts, ABO incompatibility, busulfan/cyclophosphamide conditioning and cryopreservation. In bone marrow transplants, total nucleated cell doses ⩽2.4 × 10(8) per kg were associated with PGF (odds ratio 1.39; P<0.001). The use of tacrolimus-based immunosuppression and granulocyte colony-stimulating factor were associated with decreased PGF risk. These data, allow clinicians to do more informed choices with respect to graft source, donor selection, conditioning and immunosuppressive regimens to reduce the risk of PGF. Moreover, a novel risk score determined on day 21 post transplant may provide the rationale for an early request for additional hematopoietic stem cells.

Comparison of non-myeloablative conditioning regimens for lymphoproliferative disorders.

Hematopoietic cell transplantation (HCT) with non-myeloablative (NMA) conditioning for lymphoproliferative diseases (LD) includes fludarabine with and without low-dose TBI. Transplant outcomes were compared among patients aged ⩾40 years with LD who received a HCT with TBI (N=382) or no-TBI (N=515) NMA from 2001 to 2011. The groups were comparable except for donor, graft, prophylaxis for GVHD, disease status and year of HCT. Cumulative incidences of grades II-IV GVHD at 100 days were 29% and 20% (P=0.001) and of chronic GVHD at 1 year were 54% and 44% (P=0.004) for TBI and no-TBI, respectively. Multivariate analysis of progression/relapse, treatment failure and mortality showed no outcome differences by conditioning. Full donor chimerism at day 100 was observed in 82% vs 64% in the TBI and no-TBI groups, respectively (P=0.006). Subsets of the four most common conditioning/GVHD prophylaxis combinations demonstrated higher rates of grades II-IV acute (P<0.001) and chronic GVHD (P<0.001) among recipients of TBI-mycophenolate mofetil (MMF) compared with other combinations. TBI-based NMA conditioning induces faster full donor chimerism, but overall survival outcomes are comparable to no-TBI regimens. Combinations of TBI and MMF are associated with higher rates of GVHD without impact on survival outcomes in patients with LD.

Challenges and opportunities for HSCT outcome registries: perspective from international HSCT registries experts.

Patient registries, frequently referred to as outcome registries, are 'organized systems' that use observational study methods to collect uniform data. Registries are used to evaluate specified outcomes for a population defined by a particular disease, condition or exposure that serves one or more predetermined scientific, clinical or policy purposes. Outcome registries were established very early in the development of hematopoietic SCT (HSCT). Currently, myriads of national and international HSCT registries collect information about HSCT activities and outcomes. These registries have contributed significantly to determining trends, patterns, treatment practices and outcomes. There are many different HSCT registries, each with different aims and goals; some are led by professional organizations, others by government authorities, health care providers or third parties. Some registries simply assess activity and others study outcomes. These registries are complementary and are gradually developing interoperability with each other to expand future collaborative research activities. A key development in the last few years was the incorporation of recommendations into the World Health Organization guiding principles on cell, tissue and organ transplantation. The data collection and analysis should be an integral part of therapy and an obligation rather than a choice for transplant programs. This article examines challenges in ensuring data quality and functions of outcome registries, using HSCT registries as an example. It applies to all HSCT-related data, but is predominantly focused on HSCT registries of professional organizations.

Effects of spleen status on early outcomes after hematopoietic cell transplantation.

To assess the impact of spleen status on engraftment, and early morbidity and mortality after allogeneic hematopoietic cell transplantation (HCT), we analyzed 9,683 myeloablative allograft recipients from 1990 to 2006; 472 had prior splenectomy (SP), 300 splenic irradiation (SI), 1,471 with splenomegaly (SM), and 7,440 with normal spleen (NS). Median times to neutrophil engraftment (NE) and platelet engraftment (PE) were 15 vs 18 days and 22 vs 24 days for the SP and NS groups, respectively (P<0.001). Hematopoietic recovery at day +100 was not different across all groups, however the odds ratio of days +14 and +21 NE and day +28 PE were 3.26, 2.25 and 1.28 for SP, and 0.56, 0.55, and 0.82 for SM groups compared to NS (P<0.001), respectively. Among patients with SM, use of peripheral blood grafts improved NE at day +21, and CD34+ cell dose >5.7 × 10(6)/kg improved PE at day+28. After adjusting variables by Cox regression, the incidence of GVHD and OS were not different among groups. SM is associated with delayed engraftment, whereas SP prior to HCT facilitates early engraftment without having an impact on survival.

Low-dose subcutaneous alemtuzumab in refractory chronic lymphocytic leukaemia (CLL): results of a prospective, single-arm multicentre study.

Alemtuzumab is active in chronic lymphocytic leukaemia (CLL) patients refractory to alkylators and fludarabine. The aim of this study was to determine the efficacy and safety of subcutaneous alemtuzumab at low dose (10 mg three times per week, for 18 weeks) to 49 patients with pre-treated CLL. The overall response rate was 53%, including 27% of complete responses; it was 42% in patients over 70 years, and 54% in the fludarabine-resistant patients. Forty-five percent of the patients with an unfavourable karyotype responded, including 60% of those with the 17p- aberration. After a median follow-up of 25 months, the median overall time to disease progression was 8 months (responders 12 months, non-responders 4 months). The median overall time to alternative treatment was 9 months (responders 17 months, non-responders 6 months) and median overall survival was 30 months. The treatment was well tolerated: grade IV neutropenia was observed in 17%, and cytomegalovirus (CMV) reactivation in 24% of the patients, with no CMV disease. We observed a total of 30 infections (50% during treatment and 50% during the 12-month follow-up), only one-third of which was severe. This study confirms that low-dose subcutaneous alemtuzumab is effective in poor prognosis CLL, and has a particularly favourable toxicity profile.

Cure of multiple myeloma -- more hype, less reality.

Randomized studies have firmly established the role of autologous transplant as initial therapy in multiple myeloma (MM). Indeed, MM has emerged as the commonest indication for autologous SCT in North America. The conceptual basis for high-dose therapy is the goal of complete remission (CR) through steep reduction in tumor burden affected by single and tandem transplants. Careful analysis of the data challenges the notion of CR as a surrogate to success. Intrinsically aggressive MM, defined by known unfavorable biologic risk factors, overrides the benefit of CR. In contrast, subgroups of patients with favorable biological risk factors may achieve prolonged survival, often without ever achieving CR. Unfortunately, even with tandem transplants, there is no plateau in survival curves. To this end, sequential autologous followed by nonmyeloablative allotransplants are a novel attempt at 'curing' myeloma, but the results thus far have failed to show a definite plateau in survival. Given the improvements in supportive care and concomitant reduction in transplant-related mortality, conventional myeloablative allogeneic transplants need to be re-examined as an option in high-risk aggressive myeloma. At the same time, novel antimyeloma therapies, newer risk stratification and staging tools are transforming the treatment algorithm. We examine the changing role of transplantation in myeloma in the context of novel drug therapy, biologic risk stratification and improving supportive care while arguing that the current 'one size fits all' transplant approaches are far from a cure.

Endothelial precursors and mature endothelial cells are increased in the peripheral blood of myelodysplastic syndromes.

Increased angiogenesis has been demonstrated to be a significant prognostic factor in many solid tumors. In the oncohematological setting, it has been associated with myelodysplastic syndromes (MDS), chronic myeloid leukemia, acute lymphoid, and myeloid leukemias. Recently, increased circulating endothelial cells (CECs) have been associated with breast cancer and non-Hodgkin lymphoma (NHL). Based on these premises we analysed total and activated CECs, and endothelial precursors (CEPs) in 50 MDS patients and 20 healthy donors. CECs and CEPs were quantified by flow cytometry. CEC levels were compared with bone marrow (BM) microvessel density (MVD). In addition, some angiogenic factors, namely vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and soluble VEGF-Receptor2 (VEGFR2), were tested in the sera from 25 MDS patients. Total, activated CECs and CEPs were significantly increased in MDS when compared to control group (p<0.0001); whereas in the MDS cases no association was found with French--American--British (FAB), International Prognostic Scoring System (IPSS) subtypes or survival. Patients with higher CECs also showed higher MVD. Among the cytokines analysed, sVEGFR2 was significantly higher in the lower IPSS risk classes, while the levels of bFGF directly correlated with total and activated CECs. Taken together these data strengthen the hypothesis of a possible role of angiogenesis in MDS pathogenesis.

Central venous catheter-related complications in patients with hematological malignancies: a retrospective analysis of risk factors and prophylactic measures.

UNLABELLED: We retrospectively analyzed the incidence of thrombotic and infectious complications in relation with the use of central venous catheters (CVCs), in a series of patients with hematological malignancies and low platelet and leucocyte counts. PATIENTS AND METHODS: 126 patients with hematological malignancies were analyzed. A total of 207 CVCs were implanted: 137 centrally (CICCs) and 70 peripherally (PICCs). The median duration of the CVCs was 19 days for a total of 4051 catheter-days. Antithrombotic prophylaxis was unfractionated heparin (UFH), 2,500 IU daily by 24 h continuous infusion in 169 CVCs, low molecular weight heparin (LMWH), 3,800 IU daily by single bolus intravenous injection (i.v.) in 21 and warfarin in one. No prophylaxis was given in 16 CVCs. Thrombotic complications developed in 15.5% of the CVCs (7.9 events/1000 catheter days), and the frequency of infectious complications was 10.6% (5.2 events/1000 catheter days). On multivariate analysis thromboses were more frequent and earlier with PICCs than CICCs (p = 0.0001), and in patients on UFH (16.6%) than in LMWH prophylaxis (4.7%), but the last difference was not statistically significant. In conclusions the incidence of thrombotic complications in our series was comparable to that observed in non-thrombocytopenic patients and was significantly higher in those carrying PICC than CICC (p = 0.0001). There were fewer thrombotic events in the patients receiving i.v. LMWH prophylaxis than in those receiving i.v. UFH. The use of anticoagulants was safe and not associated with hemorrhages.