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.

Recovering from chronic myeloid leukemia: the patients' perspective seen through the lens of narrative medicine.

PURPOSE: The main objective of this study is to gain a deeper understanding of how patients suffering from chronic myeloid leukemia (CML) cope with their illness. The study aims to reconstruct the subjective meaning-making process related to CML in order to gain insights into the impact the disease has on patients' emotions and everyday lives, as well as to explore the psychological impact of their being presented with the chance to suspend their therapy and recover from the disease. METHODS: Data were gathered from a qualitative study conducted in Italy on 158 Italian CML patients. Basing the study on the narrative inquiry approach, the patients were required to describe their patient journey in a qualitative narrative diary. These contained prompts to elicit the free expression of their needs, expectations, and priorities. A lexicographic analysis was carried out with T-LAB software and in particular a thematic analysis of elementary contexts (TAECs) and a word association analysis (WAA). RESULTS: The TAEC detected four thematic clusters related to two factors (temporal frame and contextual setting) that explained the variance among the narratives. The WAA evidenced a wide variety of emotions, both positive and negative, as patients reacted to the possibility of interrupting their therapy. CONCLUSIONS: A better understanding of patients' experiences can offer insights into promoting the development of more sustainable healthcare services and into therapeutic innovation aimed at improving patients' quality of life and at engaging them more in their treatment. The findings of this study can also help make medical professionals more aware of the patient's burden and help them identify potential interactions and emotional levers to improve clinical relationships.

Splanchnic vein thrombosis in myeloproliferative neoplasms: risk factors for recurrences in a cohort of 181 patients.

We retrospectively studied 181 patients with polycythaemia vera (n=67), essential thrombocythaemia (n=67) or primary myelofibrosis (n=47), who presented a first episode of splanchnic vein thrombosis (SVT). Budd-Chiari syndrome (BCS) and portal vein thrombosis were diagnosed in 31 (17.1%) and 109 (60.3%) patients, respectively; isolated thrombosis of the mesenteric or splenic veins was detected in 18 and 23 cases, respectively. After this index event, the patients were followed for 735 patient years (pt-years) and experienced 31 recurrences corresponding to an incidence rate of 4.2 per 100 pt-years. Factors associated with a significantly higher risk of recurrence were BCS (hazard ratio (HR): 3.03), history of previous thrombosis (HR: 3.62), splenomegaly (HR: 2.66) and leukocytosis (HR: 2.8). Vitamin K-antagonists (VKA) were prescribed in 85% of patients and the recurrence rate was 3.9 per 100 pt-years, whereas in the small fraction (15%) not receiving VKA more recurrences (7.2 per 100 pt-years) were reported. Intracranial and extracranial major bleeding was recorded mainly in patients on VKA and the corresponding rate was 2.0 per 100 pt-years. In conclusion, despite anticoagulation treatment, the recurrence rate after SVT in myeloproliferative neoplasms is high and suggests the exploration of new avenues of secondary prophylaxis with new antithrombotic drugs and JAK-2 inhibitors.

High rate of recurrent venous thromboembolism in patients with myeloproliferative neoplasms and effect of prophylaxis with vitamin K antagonists.

The optimal duration of treatment with vitamin K antagonists (VKA) after venous thromboembolism (VTE) in patients with Philadelphia-negative myeloproliferative neoplasms (MPNs) is uncertain. To tackle this issue, we retrospectively studied 206 patients with MPN-related VTE (deep venous thrombosis of the legs and/or pulmonary embolism). After this index event, we recorded over 695 pt-years 45 recurrences, venous in 36 cases, with an incidence rate (IR) of 6.5 per 100 pt-years (95% confidence interval (CI): 4.9-8.6). One hundred fifty-five patients received VKA; the IR of recurrent thrombosis per 100 pt-years was 4.7 (95% CI: 2.8-7.3) on VKA and 8.9 (95% CI: 5.7-13.2) off VKA (P=0.03). In patients receiving VKA, the IR of recurrent thrombosis per 100 pt-years was 5.3 (95% CI: 3.2-8.4) among 108 patients on long-term VKA and 12.8 (95% CI: 7.3-20.7) after discontinuation among the 47 who ceased treatment (P=0.008), with a doubled risk of recurrence after stopping VKA (hazard ratio: 2.21, 95% CI: 1.19-5.30). The IR of major bleeding per 100 pt-years was 2.4 (95%: CI: 1.1-4.5) on VKA and 0.7 (95% CI: 0.08-2.5) off VKA (P=0.08). In conclusion, in MPN patients with VTE recurrent thrombosis is significantly reduced by VKA and caution should be adopted in discontinuation; however, the incidence of recurrence on treatment remains high, calling for clinical trials aimed to improve prophylaxis in this setting.

Managing chronic myeloid leukaemia in the elderly with intermittent imatinib treatment.

The aim of this study was to investigate the effects of a non-standard, intermittent imatinib treatment in elderly patients with Philadelphia-positive chronic myeloid leukaemia and to answer the question on which dose should be used once a stable optimal response has been achieved. Seventy-six patients aged ⩾65 years in optimal and stable response with ⩾2 years of standard imatinib treatment were enrolled in a study testing a regimen of intermittent imatinib (INTERIM; 1-month on and 1-month off). With a minimum follow-up of 6 years, 16/76 patients (21%) have lost complete cytogenetic response (CCyR) and major molecular response (MMR), and 16 patients (21%) have lost MMR only. All these patients were given imatinib again, the same dose, on the standard schedule and achieved again CCyR and MMR or an even deeper molecular response. The probability of remaining on INTERIM at 6 years was 48% (95% confidence interval 35-59%). Nine patients died in remission. No progressions were recorded. Side effects of continuous treatment were reduced by 50%. In optimal and stable responders, a policy of intermittent imatinib treatment is feasible, is successful in about 50% of patients and is safe, as all the patients who relapsed could be brought back to optimal response.

Successful CD34+ cell mobilization by intermediate-dose Ara-C in chronic lymphocytic leukemia patients treated with sequential fludarabine and Campath-1H.

Chronic lymphocytic leukemia (CLL) cells could be undetectable by flow cytometry or polymerase chain reaction after sequential treatment with fludarabine and Campath-1H. Concern has been raised regarding the ability to mobilize sufficient peripheral blood progenitor cells (PBPCs) for autografting after purine analogues, and there are few data about PBPC collection after Campath-1H. In all, 16 CLL patients responding to sequential chemo-immunotherapy entered the study. In 10, mobilization regimen consisted of granulocyte colony-stimulating factor (G-CSF) 5-10 microg/kg/die. Patients failing mobilization or not achieving the target of 2.5 x 10(6) CD34+ cells/kg underwent a second attempt using intermediate-dose (ID) Ara-C, 800 mg/m(2) every 12 h for six doses+G-CSF. PBPC collection after G-CSF alone was successful in two out of 10 patients. An adequate number of CD34+ cells were collected after ID Ara-C+G-CSF in eight patients failing the mobilization with G-CSF alone and in five out of six who did not receive G-CSF before. Greater yields of PBPCs were collected with Ara-C+G-CSF compared with G-CSF alone (13.8 vs 3.3). The extrahematologic toxicity was manageable. In conclusion, PBPC collection is feasible in CLL patients treated with sequential therapy including fludarabine and Campath-1H. Excellent yields were obtained in 92.8% of patients primed with ID Ara-C+G-CSF.

Treatment of patients with high-grade non-Hodgkin's lymphoma aged over 70 years with an all-oral regimen combining idarubicin, etoposide and alkylators.

In elderly patients age-specific comorbidity often reduces the possibility of administering intensive chemotherapy and of obtaining response to treatment. Therefore, chemotherapy must differ from that for non-elderly patients, while maintaining the primary goal of a complete clinical response. We treated 19 patients over the age of 70 years (median age 75 years, range 70-86) with stage II-IV high-grade non-Hodgkin's lymphoma (NHL) with a combination regimen including idarubicin plus etoposide and prednimustine (or chlorambucil+prednisone), all administered orally on an outpatient basis. The therapeutic schedule included six 5-day courses of idarubicin 20 mg/sqm on day 1 (or 10 mg/sqm on days 1 and 3 in the nine patients last treated), etoposide 60 mg/sqm/12 h days 2-5, prednimustine 60 mg/sqm days 2-5, G-CSF 300 microg/day from day+7 until PMN>1000/microl. In ten patients prednimustine was replaced by chlorambucil 10 mg/sqm, days 2-5, and prednisone 50 mg days 2-5, because of non-availability of the drug. Of the 19 patients submitted to this regimen 15 (79%) obtained a clinical response: eight reached a complete response (CR), and seven a partial response (PR). Hematologic toxicity was generally mild. Only three patients had to be hospitalised for infection. Except alopecia, non-hematologic toxicities were negligible. At a median follow-up of 16 months, five of eight patients who obtained CR relapsed (median CR duration 7 months). The actuarial median survival is 34 months (range 6-46). This study demonstrates the feasibility and efficacy of an all-oral regimen including idarubicin, plus etoposide and prednimustine (or chlorambucil+prednisone) in NHL patients aged over 70 years.

The possible influences of B2A2 and B3A2 BCR/ABL protein structure on thrombopoiesis in chronic myeloid leukaemia.

The Philadelphia chromosome, t(9;22)(q34;q11) gives rise more frequently, in chronic myeloid leukaemia (CML), to two BCR/ABL chimeric transcripts differing only by the absence of 75 nucleotides and defined as b2a2 and b3a2 types, encoding two 210-kDa tyrosine kinase proteins differing only by the absence of 25 amino acids coded by the b3 exon. In the present study the two transcripts, detected by RT-PCR in 88 consecutive unselected CML patients, were correlated with haematological findings at diagnosis and with the megakaryocyte size and frequency by morphometric evaluation of 45 bone marrow biopsies. The secondary structure prediction and hydrophobicity of the b2a2 and b3a2 type BCR/ABL protein were also obtained. The prediction results for the b3 exon amino acids using GOR IV and NnPredict methods showed a short beta strand corresponding to the hydrophobic portion of the peptide. Significantly higher values were found in the platelet count of patients carrying b3a2 transcripts. The megakaryocyte size and frequency in bone marrow biopsies did not show significant differences between the two groups of patients. Stratifying the patients on the basis of white blood cell (WBC) count below or above 100x10(9)/l we still had, in both groups, a significant difference in the platelet count between the b2a2 and b3a2 patients. The possible relationships between the structure of b2a2 and b3a2 types of BCR/ABL fused protein and thrombopoiesis are discussed.

Hepato-splenic gammadelta T-cell lymphoma: a rare entity mimicking the hemophagocytic syndrome.

Hepatosplenic gammadelta T-cell lymphoma is a rare histologic type of the peripheral T-cell lymphomas, clinically characterized by predominant involvement of liver and spleen, no or little adenopathy, and an often aggressive course; it affects mainly adolescents and young adults, with a male predominance. Postthymic T-cell malignancies are heterogeneous in their clinical and laboratory features. Among the gammadelta postthymic T-cell lymphomas, two distinct entities (cutaneous and hepatosplenic, respectively) are reported in the literature. The former shows predominant multiple involvement of the skin and subcutaneous tissue; it occurs mostly in older patients and the phenotype is CD3-, CD4-, CD8-. Because of the small number of reports, the course of the disease was unknown. The latter shows a clinical picture characterized by hepatosplenomegaly, no or little adenopathy, and sometimes systemic symptoms (fever, cytopenias likely due to hypersplenism); it presents a peculiar sinusoidal involvement of liver and spleen. The bone marrow histologic feature often reveals a little infiltration, especially sinusoidal and easily underestimated phenotype: CD2+, CD3+, CD7+, CD5-, CD4-, CD8-, CD44+. Few cases of this lymphoma associated by hemophagocytic syndrome are described (Sun, 1990; Kadin, 1981; Jaffe, 1983). We report a case of a young man with a rapid and fatal course in which the more important clinical feature was hemophagocytosis. The diagnosis of lymphoma was very difficult because of paucity of histologic involvement, and only the rearrangement of TCR gamma chain gene by polymerase chain reaction on paraffin sections confirmed a clonal T-cell proliferation.

PBSC collection from G-CSF primed donors.

Peripheral blood stems cells (PBSCs) have been used in autologous transplantation as an alternative to bone marrow-derived cells. Recently, PBSCs have been collected from healthy donors after priming with G-CSF and used for allogeneic transplantation. We have a comparatively large experience with PBSC collection in autologous and allogeneic settings. The five cell separators we employ are: the CS3000 plus, AS 104, Excel, Cobe Spectra and MCS 3p. These machines appear to have different efficacies but no studies have been carried out on this topic. In a prospective study we have randomly assigned donors to different cell separators to evaluate their efficiency. Twenty-five donors underwent the procedure and 50 leukaphereses were carried out. Donors were given 5 micrograms kg-1 d-1 of recombinant human G-CSF for 3 days and 10 micrograms kg-1 d-1 for 4 days subcutaneously. Leukaphereses were performed on days 6 and 7 of G-CSF administration. The results of our study show that a total value of CD34+ cells ranging from 48.44 x 10(6) to 270.37 x 10(6) can be collected from donors with a white cell count ranging from 40.50 x 10(3) microL-1 to 51.34 x 10(3) microL-1 and mononuclear cells ranging from 16.42 to 20.37%. The Excel and the MCS 3p seem to differ from the other machines in terms of higher CD34+ cell collection efficiency. The Excel appears to be even more efficient than the MCS 3p, but this may not reflect reality because the Excel processes 12 L of blood while the MCS 3p employs an 8 L procedure. All the machines showed satisfactory results in terms of yield and quality of the harvests.

Twelve years experience with high-dose therapy and autologous stem cell transplantation for high-risk Hodgkin's disease patients in first remission after MOPP/ABVD chemotherapy.

High-dose therapy followed by autografting can cure patients with aggressive Hodgkin's disease (HD) refractory or with early relapse to first-line combination chemotherapy. On the other hand, the eradication of the disease is rarely achieved in heavily pretreated patients. It has been suggested that patients with HD with very high risk characteristics at diagnosis, often relapse despite appropriate therapy with 7-8 drugs combination. Thus it seems to us that such patients are potential candidates for early autografting during first remission. Twelve years ago, we initiated a pilot study to investigate whether patients with very high risk characteristics, would benefit from early autografting. The application of early autografting was compared with our historical group of patients in complete remission after receiving MOPP/ABVD, who had the same negative prognostic characteristics, refused autografting and who did not receive other treatment after achieving complete remission. Among the 22 consecutive patients entered into the pilot study and autografted, 18 are alive and 17 (77%) remain alive in unmaintained remission at a median of 86 months. One patient (4%) died of interstitial pneumonitis in the transplantation group. Only 8/24 (33%) patients, who did not receive an autograft, are currently alive and disease free at a median of 89 months. In conclusion, the early application of autografting appears to improve the outcome in patients with very high risk HD who achieved remission with MOPP/ABVD.

Philadelphia-chromosome-negative peripheral blood stem cells can be mobilized in the early phase of recovery after a myelosuppressive chemotherapy in Philadelphia-chromosome-positive acute lymphoblastic leukaemia.

Ten patients in first or second relapse with Philadelphia chromosome acute lymphoblastic leukaemia, ineligible for allogeneic sibling marrow transplantation, were treated with an intensive chemotherapy regimen including idarubicin, intermediate-dose arabinosylcytosine, etoposide and G-CSF. Peripheral blood stem cells were collected by leukapheresis during initial early WBC recovery from chemotherapy-induced aplasia. In 5/10 patients all metaphases in leukapheresis products were found to be Philadelphia-chromosome-negative and they have been used as autotransplants after conditioning with TBI/etoposide/cyclophosphamide (or idarubicin) and G-CSF. All five patients showed sustained engraftment and one of them is alive and well Philadelphia-chromosome-negative 18 months after transplant. These preliminary results suggest that it is possible to recover Philadelphia-chromosome-negative blood stem cells after intensive chemotherapy, even in advanced patients, and to perform autografting with these cells.

Idarubicin, intermediate-dose cytarabine, etoposide, and granulocyte-colony-stimulating factor are able to recruit CD34+/HLA-DR- cells during early hematopoietic recovery in accelerated and chronic phases of chronic myeloid leukemia.

A group of 46 patients with chronic myelogenous leukemia (CML) [chronic phase (CP), 24 patients; accelerated phase (AP), 22 patients] ineligible for allogeneic bone marrow transplantation were given an intensive chemotherapy regimen consisting of idarubicin, intermediate-dose cytarabine, and etoposide. All patients had previously received interferon-alpha and only 2 had shown a partial cytogenetic response. During early recovery from chemotherapy-induced aplasia, peripheral blood progenitor cells (PBPC) were harvested by leukapheresis. All metaphases were found to be Philadelphia chromosome (Ph) negative in the collection from 17 of 46 (37%) patients [CP, 12 of 24 (50%); AP, 5 of 22 (23%)], and a decrease to less than 50% Ph-positive metaphases was seen in an additional 6 (CP, 3 patients; AP, 3 patients). The percentage of patients showing complete Ph disappearance was 64% in those receiving this procedure within the first year of diagnosis. In vitro studies were performed to assess the behavior of the Ph-negative PBPC. In clonogenic cultures they responded to stem cell factor and were able to grow as mixed colonies. Moreover, long-term culture initiating cells (LTCIC) were present in many Ph-negative collections but rarely in Ph-positive PBPC. In 4 females, clonality was studied by analyzing X chromosome inactivation and methylation patterns of the DXS255 locus with the probe M27 beta. Hematopoiesis was polyclonal in all 4 patients tested. Thus far, the Ph-negative collections have been used for autografting in 16 patients (CP, 11 patients; PA, 5 patients) after conditioning with total-body irradiation, etoposide, and cyclophosphamide or idarubicin.(ABSTRACT TRUNCATED AT 250 WORDS)

Selective overshoot of Ph-negative blood hemopoietic cells after intensive idarubicin-containing regimen and their repopulating capacity after reinfusion.

Twenty-seven patients with chronic myelogenous leukemia (CML)--17 in the chronic phase and 10 in the accelerated phase--were treated with an intensive chemotherapy regimen consisting of idarubicin, arabinosylcytosine, and etoposide. All patients were ineligible for bone marrow transplantation (BMT) and showed little or no cytogenetic response to interferon alpha (IFN-alpha). Blood hemopoietic cells (BHC) were collected by leukapheresis in all patients during early recovery from chemotherapy-induced aplasia. In 13/27 patients (48%), all metaphases were Ph-negative (Ph-); in another five patients, the percentage of Ph-positive (Ph+) metaphases decreased to less than 50%. Complete Ph+ disappearance was found in 66% of the patients treated within two years of diagnosis and in only 30% of those treated later. The collected Ph- cells have been used as autotransplants in nine patients: seven have shown sustained engraftment, and five are alive and well, with Ph- at 3+, 4+, 7+, 11+, and 19+ months after transplant. It is remarkable that one patient, now Ph- at 19 months after transplant, is also PCR negative. These results suggest that it is possible to collect Ph- hemopoietic cells even years after diagnosis and to perform autologous transplants with these cells.

Collection of 'normal' blood repopulating cells during early hemopoietic recovery after intensive conventional chemotherapy in chronic myelogenous leukemia.

Twenty-five patients with CML (chronic phase (CP): 15 patients; accelerated phase (AP): 10 patients) at a median of 40 months after diagnosis and ineligible for allogeneic BMT, received an intensive chemotherapy regimen consisting of idarubicin, intermediate-dose ara-C and etoposide (ICE protocol). All patients had previously received alpha-interferon and only two patients had had partial cytogenetic response. During recovery from chemotherapy-induced aplasia, blood progenitors cells (BPC) were harvested by leukapheresis. All metaphases were found to be Ph-negative in the collection of 12 of 25 (48%) patients (CP: 9 of 15 (60%), AP: 3 of 10 (30%)) and a decrease of < 50% Ph-positive metaphases was seen in an additional five (CP: 4 patients; AP: 1 patient). The percentage of complete Ph-disappearance was 66% in patients receiving this procedure within the first 2 years of diagnosis and 30% in those treated after the second year of diagnosis. So far, the Ph-negative collections have been used in 9 patients (CP: 8 patients; AP: 1 patient) as autograft after conditioning with total body irradiation/etoposide/CY. Seven of 9 patients engrafted and 5 are alive and well, Ph-negative at 2+, 3+, 6+, 10+ and 18+ months.