Treatment-free remission in chronic myeloid leukemia patients treated front-line with nilotinib: 10-year followup of the GIMEMA CML 0307 study.

We report the final analysis, with a 10-year follow-up, of the phase II study GIMEMA CML 0307 (NCT00481052), which enrolled 73 adult patients (median age 51 years; range, 18-83) with newly diagnosed chronic-phase chronic myeloid leukemia to investigate the efficacy and the toxicity of front-line treatment with nilotinib. The initial dose was 400 mg twice daily; the dose was reduced to 300 mg twice daily as soon as this dose was approved and registered. The 10-year overall survival and progression- free survival were 94.5%. At the last contact, 36 (49.3%) patients were continuing nilotinib (22 patients at 300 mg twice daily, 14 at lower doses), 18 (24.7%) patients were in treatment-free remission, 14 (19.2%) were receiving other tyrosinekinase inhibitors and four (5.5%) patients have died. The rates of major and deep molecular responses by 10 years were 96% and 83%, respectively. The median times to major and deep molecular response were 6 and 18 months, respectively. After a median duration of nilotinib treatment of 88 months, 24 (32.9%) patients discontinued nilotinib while in stable deep molecular response. In these patients, the 2-year estimated treatment-free survival was 72.6%. The overall treatment-free remission rate, calculated on all enrolled patients, was 24.7% (18/73 patients). Seventeen patients (23.3%), at a median age of 69 years, had at least one arterial obstructive event. In conclusion, the use of nilotinib front-line in chronic phase chronic myeloid leukemia can induce a stable treatment-free remission in a relevant number of patients, although cardiovascular toxicity remains of concern.

Health-related quality of life in patients with chronic myeloid leukemia receiving first-line therapy with nilotinib.

BACKGROUND: Although a wealth of efficacy and safety data is available for many tyrosine kinase inhibitors used in chronic myeloid leukemia (CML), there is a dearth of information on their impact on patients' health-related quality of life (HRQOL). The primary objective of this study was to evaluate HRQOL and fatigue outcomes in patients with CML receiving first-line therapy with nilotinib. METHODS: This was a multicenter, prospective study enrolling 130 patients with chronic-phase CML. HRQOL and fatigue were evaluated with the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) and its validated Fatigue module at the baseline and then at 3, 6, 12, 18, and 24 months. The primary prespecified HRQOL endpoints defined in the study protocol for longitudinal analysis were the Physical Functioning, Social Functioning, Role Functioning, and Fatigue scales. The remaining scales were investigated on an exploratory basis. RESULTS: The rate of baseline compliance with the HRQOL assessment was 95.4% (124 of 130), and the rate of overall compliance with HRQOL forms was 91%. Among the 4 prespecified primary HRQOL endpoints, statistically significant improvements over time were found for Physical Functioning (P = .013), Role Functioning (P = .004), and Fatigue (P < .001). Clinically meaningful improvements were found already 3 months after the treatment start. The baseline patient self-reported fatigue severity was an independent predictive factor for the achievement of a major molecular response with an odds ratio of 0.960 (95% confidence interval, 0.934-0.988; P = .005). CONCLUSIONS: For most patients, HRQOL improvements with nilotinib occur during the early phase of therapy and are maintained over time. Also, a more systematic HRQOL evaluation during the diagnostic workup of CML may help to predict clinical outcomes. Cancer 2018;124:2228-37. © 2018 American Cancer Society.

A population-based study of chronic myeloid leukemia patients treated with imatinib in first line.

Chronic myeloid leukemia (CML) treatment is based on company-sponsored and academic trials testing different tyrosine kinase inhibitors (TKIs) as first-line therapy. These studies included patients selected according to many inclusion-exclusion criteria, particularly age and comorbidities, with specific treatment obligations. In daily clinical practice (real-life), inclusion-exclusion criteria do not exist, and the treatment outcome does not only depend on the choice of first-line TKI but also on second- and third-line TKIs. To investigate in a real-life setting the response and the outcome on first-line imatinib, with switch to second generation TKIs in case of unsatisfying response or intolerance, we analyzed all newly diagnosed patients (N = 236), living in two Italian regions, registered in a prospective study according to population-based criteria and treated front-line with imatinib. A switch from imatinib to second-generation TKIs was reported in 14% of patients for side effects and in 24% for failure or suboptimal response, with an improvement of molecular response in 57% of them. The 5-year overall survival (OS) and leukemia-related survival (LRS) were 85% and 93%, respectively; the 4-year rates of MR3.0 and MR4.0 were 75% and 48%, respectively. Cardiovascular complications were reported in 4% of patients treated with imatinib alone and in 6% of patients receiving nilotinib as second-line. Older age (≥70 years) affected OS, but not LRS. These data provide an unbiased reference on the CML management and on the results of TKI treatment in real-life, according to ELN recommendations, using imatinib as first-line treatment and second-generation TKIs as second-line therapy. Am. J. Hematol. 92:82-87, 2017. © 2016 Wiley Periodicals, Inc.

Nilotinib 300 mg twice daily: an academic single-arm study of newly diagnosed chronic phase chronic myeloid leukemia patients.

The introduction and the extended clinical use of nilotinib in the first-line treatment of chronic myeloid leukemia have been based on company-sponsored trials. Independent confirmations are extremely important. We report an investigator-sponsored study of nilotinib 300 mg twice daily in 130 chronic myeloid leukemia patients in early chronic phase. A deep molecular response was achieved in 46% (MR4.0) and 17% (MR4.5) of patients at 2 years; 58% of the enrolled patients achieved a MR4.0 at least once, with a sustained MR4.0 in 52% of them. With a median observation of 29 months (range 24-37 months), 77% of patients were still on treatment with nilotinib. The reasons for permanent discontinuation were: 3% progression, 5% failure or suboptimal response, 8% adverse events, 1% treatment-free remission, and 5% other reasons. Thirteen thrombotic arterial events were reported in 12 patients. A prospective evaluation of metabolic effects showed an increase of fasting glucose without significant variations of glycated hemoglobin, an increase of total cholesterol (both low density lipoprotein and high density lipoprotein fractions) and a decrease of triglycerides. This study confirms a high and rapid efficacy of nilotinib 300 mg twice daily and provides detailed information on the type and incidence of non-hematologic and metabolic adverse events (clinicaltrials.gov identifier: 01535391).

Personal history and quality of life in chronic myeloid leukemia patients: a cross-sectional study using narrative medicine and quantitative analysis.

BACKGROUND: Tyrosine kinase inhibitors (TKIs) drastically changed the outcome of patients diagnosed with chronic myeloid leukemia (CML). Several reports indicated the advantage of continue long-term adherence associated with positive outcome. Therefore, it is important to better understand from the patient's standpoint the experience of living with the disease and the related treatment. OBJECTIVES: In this study, quantitative analysis and narrative medicine were combined to get insights on this issue in a population of 257 patients with CML in chronic phase treated with TKIs (43 % men, with a median age of 58 years, 27 % aged 31-50 years), followed for a median time of 5 years. Sixty-one percent of patients enrolled were treated in first line, whereas 37 % were treated in second line. RESULTS: The results showed more positive perceptions and acceptance in males compared to females, without impact of disease on relationships. Level of positive acceptance was more evident in elderly compared to younger patients, with a close connection with median time from diagnosis. Overall, female patients reported negative perceptions and an impact of disease on family daily living. The majority of patients understood the importance of continue adherence to treatment, with 27 % resulting less adherent (60 % for forgetfulness), even if well informed and supported by his/her physician. DISCUSSION AND CONCLUSIONS: Narrative medicine, in association to quantitative analysis, can help physicians to understand needs of their patients in order to improve communication.

Long-term outcome of a phase 2 trial with nilotinib 400 mg twice daily in first-line treatment of chronic myeloid leukemia.

Nilotinib is a second-generation tyrosine kinase inhibitor that has been approved for the first-line treatment of chronic-phase chronic myeloid leukemia, based on the results of a prospective randomized study of nilotinib versus imatinib (ENESTnd). Apart from this registration study, very few data are currently available on first-line nilotinib treatment. We report here the long-term, 6-year results of the first investigator-sponsored, GIMEMA multicenter phase 2, single-arm trial with nilotinib 400 mg twice daily as first-line treatment in 73 patients with chronic-phase chronic myeloid leukemia. Six-year overall survival and progression-free survival rates were 96%, with one death after progression to blast phase. At 6 years, 75% of the patients were still on nilotinib. The cumulative incidence of major molecular response was 98%; only one patient had a confirmed loss of major molecular response. The cumulative incidence of deep molecular response (MR 4.0) was 76%. Deep molecular response was stable (≥ 2 years) in 34% of these patients. Cardiovascular adverse events, mainly due to arterial thrombosis, occurred in 11/73 patients (15%), after 24 to 76 months of therapy. They were more frequent in elderly patients, and in those with baseline cardiovascular risk factors. None was fatal, although there was a relevant morbidity. This is the study with the longest follow-up of a high dose of nilotinib (400 mg twice daily): it highlights the high efficacy and the cardiovascular toxicity of the drug (CTG.NCT.00481052).

Long term outcome of Ph+ CML patients achieving complete cytogenetic remission with interferon based therapy moving from interferon to imatinib era.

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 unnecessary for such a long survival. This study further supports development of studies testing the clinical effect of the combinations of TKIs with IFNα.

Making Treatment-Free Remission (TFR) Easier in Chronic Myeloid Leukemia: Fact-Checking and Practical Management Tools.

In chronic-phase chronic myeloid leukemia (CML), tyrosine kinase inhibitors (TKIs) are the standard of care, and treatment-free remission (TFR) following the achievement of a stable deep molecular response (DMR) has become, alongside survival, a primary goal for virtually all patients. The GIMEMA CML working party recently suggested that the possibility of achieving TFR cannot be denied to any patient, and proposed specific treatment policies according to the patient's age and risk. However, other international recommendations (including 2020 ELN recommendations) are more focused on survival and provide less detailed suggestions on how to choose first and subsequent lines of treatment. Consequently, some grey areas remain. After literature review, a panel of Italian experts discussed the following controversial issues: (1) early prediction of DMR and TFR: female sex, non-high disease risk score, e14a2 transcript and early MR achievement have been associated with stable DMR, but the lack of these criteria is not sufficient to exclude any patient from TFR; (2) criteria for first and subsequent line therapy choice: a number of patient and drug characteristics have been proposed to make a personalized decision; (3) monitoring of residual disease after discontinuation: after the first 6 months, the frequency of molecular tests can be reduced based on MR4.5 persistence and short turnaround time; (4) prognosis of TFR: therapy and DMR duration are important to predict TFR; although immunological control of CML plays a role, no immunological predictive phenotype is currently available. This guidance is intended as a practical tool to support physicians in decision making.

Development of hypogammaglobulinemia in patients treated with imatinib for chronic myeloid leukemia or gastrointestinal stromal tumor.

Imatinib mesylate is a tyrosine kinase inhibitor used as first line treatment in chronic myeloid leukemia and gastrointestinal stromal tumor patients. Although several in vitro and animal studies demonstrated that imatinib affects immune response, few immune alterations are described in humans. We retrospectively studied hematologic and immunological parameters in 72 chronic myeloid leukemia and 15 gastrointestinal stromal tumor patients treated with imatinib at standard dosage and in 20 chronic myeloid leukemia patients treated before the introduction of imatinib in clinical practice. Both chronic myeloid leukemia and gastrointestinal stromal tumor patients developed a significant reduction of gammaglobulin and immunoglobulin serum levels. No significant hypogammaglobulinemia was observed in chronic myeloid leukemia patients in the pre-imatinib era. These data demonstrate that imatinib treatment induces hypogammaglobulinemia that can reach a severe entity in 10% of cases, both in chronic myeloid leukemia and in gastrointestinal stromal tumor patients. Prospective studies are needed to evaluate immune humoral alterations and to define the real incidence of infectious events, including viral reactivations.

Role of anti-hepatitis C virus (HCV) treatment in HCV-related, low-grade, B-cell, non-Hodgkin's lymphoma: a multicenter Italian experience.

PURPOSE: Hepatitis C virus (HCV) is endemic in some areas of Northwestern Europe and the United States. HCV has been shown to play a role in the development of both hepatocellular carcinoma and B-cell non-Hodgkin's lymphoma (B-NHL). The biologic mechanisms underlying the lymphomagenic activity of the virus so far are under investigation. In this study, the role of antiviral (anti-HCV) treatment in B-NHL associated with HCV infection is evaluated. PATIENTS AND METHODS: Thirteen patients with histologically proven low-grade B-NHL characterized by an indolent course (ie, doubling time no less than 1 year, no bulky disease) and carrying HCV infection were enrolled on the study. All patients underwent antiviral treatment alone with pegilated interferon and ribavirin. Response assessment took place at 6 and 12 months. RESULTS: Of the twelve assessable patients, seven (58%) achieved complete response and two (16%) partial hematologic response at 14.1 +/- 9.7 months (range, 2 to 24 months, median follow-up, 14 months), while two had stable disease with only one patient experiencing progression of disease. Hematologic responses (complete and partial, 75%) were highly significantly associated to clearance or decrease in serum HCV viral load following treatment (P = .005). Virologic response was more likely to be seen in HCV genotype 2 (P = .035), while hematologic response did not correlate with the viral genotype. Treatment-related toxicity did not cause discontinuation of therapy in all but two patients, one of whom, however, achieved complete response. CONCLUSION: This experience strongly provides a role for antiviral treatment in patients affected by HCV-related, low-grade, B-cell NHL.

ABL mutations in late chronic phase chronic myeloid leukemia patients with up-front cytogenetic resistance to imatinib are associated with a greater likelihood of progression to blast crisis and shorter survival: a study by the GIMEMA Working Party on Chronic Myeloid Leukemia.

PURPOSE: Point mutations within the ABL kinase domain of the BCR-ABL gene have been associated with clinical resistance to imatinib mesylate in chronic myeloid leukemia (CML) patients. To shed further light on the frequency, distribution, and prognostic significance of ABL mutations, we retrospectively analyzed a homogeneous cohort of late chronic phase CML patients who showed primary cytogenetic resistance to imatinib. PATIENTS AND METHODS: Using denaturing high-performance liquid chromatography (D-HPLC) and sequencing, we screened for ABL mutations in a total of 178 bone marrow and/or peripheral blood samples from 40 late chronic phase CML patients homogeneously treated with imatinib 400 mg/d, who did not reach a major cytogenetic response at 12 months. RESULTS: Mutations were found in 19 of 40 patients (48%). Mutations were already detectable by D-HPLC at a median of 3 months from the onset of therapy. The presence of a missense mutation was significantly associated with a greater likelihood of subsequent progression to accelerated phase/blast crisis (P = .0002) and shorter survival (P = .001). Patients carrying mutations falling within the P-loop seemed to have a particularly poor outcome in terms of time to progression (P = .032) and survival (P = .045). CONCLUSION: Our results show that, irrespective of the hematologic response, monitoring for emerging mutations in the first months of therapy may play a role in detecting patients with worse prognosis, for whom a revision of the therapeutic strategy should be considered.

Primary pancreatic lymphoma. Report of five cases.

Primary pancreatic lymphoma (PPL) is a very rare disease. We report five cases of PPL (4 men and 1 woman, mean age 65 years) diagnosed and treated at our Institution from 1987 to 1997. None of these patients had evidence of extrapancreatic disease and they were categorized as PPL involving pancreas only (stage IE, 3 patients) or pancreas and peripancreatic lymph nodes (stage IIE, 2 patients). The most common presenting symptoms were abdominal pain and weight loss. Imaging techniques showed a mass of the pancreatic head in all cases. The histological diagnosis (3 diffuse-large cell non-Hodgkin's lymphoma and 2 lymphoplasmacytic lymphoma/immunocytoma) was made by ultrasound-guided fine needle aspiration biopsy and tissue core fine-needle biopsy in three patients and by surgery in the remaining two patients. The three patients diagnosed by percutaneous biopsy were treated with chemotherapy as front-line therapy and two of them received also local radiotherapy; one of these patients is still alive in complete remission at 69 months, one died of an unrelated disease at 67 months and one died of lymphoma relapse at 88 months. Two patients underwent pancreaticoduodenectomy plus adjuvant chemotherapy; one of them died of recurrent cholangitis 8 months after surgery while the other one is still alive in complete remission after 160 months. This study shows that: 1) imaging techniques can suggest the suspicion of PPL but are unable to distinguish PPL from pancreatic adenocarcinoma; 2) histological diagnosis can be easily obtained by percutaneous US-guided tissue core biopsy; 3) surgery can be avoided both for diagnosis and therapy but the treatment of choice of PPL may only be evaluated on a larger series of patients.

Safety and efficacy of granulocyte colony-stimulating factor biosimilars in engraftment after autologous stem cell transplantation for haematological malignancies: a 4-year, single institute experience with different conditioning regimens.

BACKGROUND: Filgrastim biosimilars have recently been introduced into clinical practice. To date biosimilars have demonstrated comparable efficacy and safety as the originator in chemotherapy-induced neutropenia. Published experience in engraftment after autologous stem cell transplantation (ASCT) is limited and concerns relatively few patients. MATERIALS AND METHODS: With the aim of assessing the efficacy and the safety of filgrastim biosimilars in post-ASCT bone marrow recovery, we conducted a single institution, retrospective study in 56 lymphoma and myeloma patients who received filgrastim biosimilars (Tevagrastim(®) and Zarzio(®)) at standard doses from day 5. We compared our results with recently published data on the originator. A cost analysis of each biosimilar was performed. RESULTS: Neutrophil counts recovered in 55 patients. The median number of filgrastim biosimilar vials injected was seven per patient. The median time to neutrophil and platelet recovery was 10 and 12 days, respectively. Twenty-six patients had febrile neutropenia, in half of whom the agent involved was identified. In the cost analysis, the use of Tevagrastim(®) and Zarzio(®) was associated with cost reductions of 56% and of 86%, respectively. DISCUSSION: Despite differences in CD34+ cell counts and time of starting filgrastim, our results in terms of time to engraftment and median number of vials injected are similar to published data. Comparing our results by single conditioning regimen to recent literature data, the time to engraftment and duration of hospitalisation were equivalent. Significant differences were observed in the incidence of febrile neutropenia, perhaps due to different preventive and prophylactic protocols for infections. Although prospective studies should be performed to confirm our results, filgrastim biosimilars were found to be effective and safe in engraftment after ASCT.

Primary lung lymphoma.

Lymphoproliferative disorders affecting the lung are infrequent. Therefore the diagnosis is often not easy, specially when the lung is primary affected. Moreover, new clinical-pathological entities are responsible of primary lung lymphoma that require specific treatment. It is important to keep in mind the chance that lung may be involved by lymphoproliferative disorders so to avoid the mistake of the misdiagnosis of this curable diseases since sometimes they have a good prognosis and a very different management from epithelial neoplasia of the lung.

Inversion time prolongation at late enhancement cardiac MRI in a myeloma patient.

A patient undergoing chemotherapy for multiple myeloma had a sudden onset of heart failure. Cardiac magnetic resonance was performed after echocardiography to rule out myocardial late enhancement, which was not detected. In- terestingly, the inversion time of the T1-weighted inversion recovery late enhancement sequence needed to be significantly increased (from the usual 250-300 to 490 ms) to obtain diagnostic images. This report presents the clinical case of this patient, and discusses potential implications.

Risk and early cytogenetic response to imatinib and interferon in chronic myeloid leukemia.

BACKGROUND AND OBJECTIVES: We compared the early cytogenetic response (CgR) to a combination of imatinib mesylate (Glivec, Novartis Pharma, Basel, Switzerland) and a pegylated form of human recombinant interferon-alpha2b (pegIFN-alpha2b, PegIntron, Schering Plough, Kenilworth, New Jersey, USA) with the relative risk, either according to Sokal's or Euro scoring systems. DESIGN AND METHODS: Seventy-seven patients with early chronic phase, previously untreated, Ph-positive chronic myeloid leukemia (CML) received a combination of imatinib mesylate (400 mg/day) and pegIFN-alpha2b (3 consecutive cohorts treated with 50, 100 or 150 mg/weekly). Fifty-seven patients have completed the first 6 months of treatment and are evaluable for CgR. RESULTS: After 6 months of treatment, the overall major CgR rate was 89% and 90% in low risk patients (Sokal's and Euro, respectively), 76 and 59% in intermediate risk and 23% and 17% in high risk patients. These differences were significant (p=0.0001 for Sokal and 0.001 for e). INTERPRETATION AND CONCLUSIONS: For the first time, these data suggest that the early CgR rate to a imatinib mesylate-based regimen is significantly risk-related.

Molecular response to imatinib in late chronic-phase chronic myeloid leukemia.

Imatinib is a tyrosine-kinase inhibitor that binds to ABL proteins and induces cytogenetic remissions in patients with chronic myeloid leukemia (CML). In these patients measuring response by molecular techniques is clearly required. We determined the cytogenetic and molecular response (CgR, MR) to imatinib in 191 patients with late chronic-phase Philadelphia-positive (Ph+) CML, previously treated with interferon alpha. MR was assessed with real-time quantitative (TaqMan) reverse transcription-polymerase chain reaction and was expressed as the ratio between BCR/ABL and beta 2-microglobulin x 100, the lowest level of detectability of the method being 0.00001. A complete CgR (CCgR) was achieved in 85 (44%) of 191 patients and was maintained for 2 years in 67 (79%) of 85 patients. A reduction of the transcript level of more than 2 logs was achieved in all but 9 patients with CCgR versus none of 23 with partial CgR. In the CCgRs the median value of the MR was 0.0008 after 12 months and 0.0001 after 24 months, with the transcript level undetectable in 22 cases. We conclude that in CCgRs the degree of MR may vary from 2 to more than 4 logs, and that there is a progressive decrease of transcript level by time. Only 1 of 22 negative cases has had a relapse as yet.