ABSTRACT
Background: Secondary antibody deficiency (SAD) is typical of hematological malignancies, such as chronic lymphocytic leukemia (CLL), multiple myeloma, and lymphoma or as a side effect of their treatment. Immunological defects are observed in 25-85% of CLL patients (pts), both naïve and previously treated, depending on duration, stage of disease, treatment, patient's age, and comorbidities. (Na et al., 2019;Patel et al., 2019;Zinzani et al., 2019;Reiser et al., 2017). In CLL pts, SAD increases the risk of infections, with overall higher morbidity and mortality Antibiotics administration and vaccinations are recommended as risk-reduction strategies. No real guidelines are available, but many indications warrant immunoglobulins replacement therapy (IgRT) in selected pts with low IgG (<5 g/l) or with more than three infective episodes per year despite antibiotic treatment and timely vaccination (Na et al., 2019;Reiser et al., 2017). No clear indications are available regarding the delivery method (intravenous or subcutaneous), dosage, frequency of administration, and duration of IgRT. Aims: The aim of this study is to assess the efficacy and the safety of SCIg on CLL patients in terms of infectious events, immune recovery and lymphocytes subset, impact on quality of life (QoL) on CLL pts in the Covid-19 era. Methods: Ten CLL pts with SAD have been treated with subcutaneous IgRT (SCIg) from October 2019 to December 2020. The median age and body weight of the pts were 66 years (56-88) and 68 kg (52-86) respectively. Five patients had comorbidities (hypertension, diabetes mellitus, and lung diseases) and 90% of them had an Eastern Cooperative Oncology Group (ECOG) performance 0-1. Five pts presented with unmutated IgVH and one of them also had 17p deletion. The median number of prior therapies was 2 (IBR, BR, Chl-antiCD20, FCR, in 5, 4, 4, 3 pts, respectively). At that time, 7 pts were on therapy (IBR, Ven, Alkylating Agent in 4, 1, 2 pts, respectively). None presented neutropenia. All pts underwent antibiotic prophylaxis with trimetroprin-cotimoxazole, sometimes associated with clarithromycin, and influenza vaccinations. The median baseline IgG level was 485mg/dl (118-817), with a median of 3 infection/year (1-5;pneumonia, UTI). Patients' characteristics are reported in Table 1. All pts received 10 g total dose hyaluronidase-free SCIg over a 1 h in double-needle subcutaneous infusion every 15 days for one year, independently from body weight. After the first dose, administered in a hospital setting to make the patient comfortable with their personal pump, the next doses were self-administered at home. The IgG level and CD4/CD8, CD19, and CD16/56 (natural killer, NK) lymphocytes subset were recorded at baseline and every three months during the observation period to monitor the immunological reconstitution as the therapy went on. Results: In our monocentric experience from October 2019 to December 2020 no patient experienced infectious events nor Covid-19 mediated interstitial pneumonia while on SCIg therapy. All patients tolerated well the therapy: nobody interrupted the treatment and only one patient presented a skin rash (grade 2). Both dosage and administration schedule have been stable over time. Dealing with humoral immunity, IgG levels arose from a median of 485 (118-817) mg/dl to a stable median value >600 mg/dl from 6 months onward. As expected, IgA and IgM values remained below normal levels. Dealing with cellular immunity, T-cells including CD4, CD8, and natural killer (NK, CD16/56) cells displayed a stable fashion until 6 months. On the other hand, the CD19 B cells values reflect both the disease status and the ongoing treatment effects. Results are reported in Table 1. Finally, we observed advantages on adherence to treatment, QoL, and costs, since pts did not need to go to the hospital with the help of a care-giver, rather they could comfortably get their SCIg at home without any assistance. Conclusion: SCIg administration in CLL pts with SAD is efficacious and safe as infectious prophylaxis, with hig er median IgG levels, thanks to both pharmacokinetic advantages and improved adherence to treatment. Especially in the Covid-19 era, the subcutaneous route is preferred to the intravenous one, because of the self-administration at home and the granted availability to the drug itself. Finally, subcutaneous administration gives advantages to the QoL and hospital expenditure.
ABSTRACT
Background: Secondary antibody deficiency (SAD) is a typical manifestation of haematological malignancies such as chronic lymphocytic leukaemia (CLL), or a side effect of their treatment. Immunological defects are observed in 25-85% of CLL patients (pts) and increases the risk of infections, with overall higher morbidity and mortality. Antibiotics administration and vaccinations are recommended as risk-reduction strategies in those pts. No real guidelines are available to recommend eligibility for prophylaxis, but many indications warrant immunoglobulins replacement therapy (IgRT) in selected pts with low IgG (<5g/l) or with more than 3 infective episodes per year despite antibiotic treatment and timely vaccination. No clear indications are available regarding the delivery method (intravenous or subcutaneous), dosage, frequency of administration and duration of IgRT. Aims: The aim of this study is to assess the efficacy and safety of subcutaneous IgRT (SCIg) and its impact on quality of life (QoL) on CLL pts in Covid-19 era. Methods: Ten CLL pts, have been treated with SCIg from October 2019 to December 2020. Median age and body weight were 66 years (56-88) and 68 Kg (52-86). Comorbidities were present in 5 pts (hypertension, diabetes mellitus, lung diseases). 5 pts had unmutated IgVH and 1 had 17p deletion. The median number of prior therapies was 2 (IBR, BR, Chl-antiCD20, FCR, in 5, 4, 4, 3 pts respectively). At that time, 7 pts were on therapy (IBR, Ven, Alkylating Agent in 4, 1, 2 pts respectively). None presented neutropenia. All pts underwent antibiotic prophylaxis with trimetroprin-cotimoxazole, sometimes associated with clarithromycin, and influenza vaccinations. Median baseline IgG level was 485 mg/dl (118-817), with a media of 3 infection/year (1-5;pneumonia, UTI). All pts received 10 g total dose hyaluronidase-free SCIg over a 1h double-needle subcutaneous infusion every 15 days over one year, independently from their body weight. After the first dose, administered in a hospital setting to make the patient comfortable with their personal pump, the next doses were self-administered at home. The IgG level and CD4/CD8, CD19 and CD16/56 (natural killer, NK) lymphocytes subset were recorded both at baseline and during the observation period to monitor the immunological reconstitution as the therapy went on. Results: No patient experienced infectious events during the SCIg therapy nor Covid-19 mediated interstitial pneumonia. All patients tolerated the therapy: nobody interrupted the treatment and only one patient presented a skin rash (grade 2). Both dosage and administration schedule have been stable over time. Dealing with humoral immunity, IgG levels arose from a median of 485 mg/dl (118-817) to a stable median value >600 mg/dl from 6 months onward. About cellular immunity, T-cells including CD4 and CD8 and NK cells displayed a stable fashion until 6 months. On the other hand, the CD19 B cells values reflect both the disease status and the ongoing treatment effects. Results were in Table 1. Finally we observed advantages on both QoL and costs, since pts did not need to go to the hospital with the help of a care-giver, rather they could comfortably get their SCIg at home without any assistance. Summary/Conclusion: SCIg administration in CLL pts is safe and efficacious as infectious prophylaxis, with higher median IgG levels, thanks to its pharmacokinetic advantages and improved adherence to treatment. Especially in the Covid-19 era, the subcutaneous route is preferred to the intravenous one, because of the self-administration at home and the granted availability to the drug itself.
ABSTRACT
Background: An outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) started in December 2019 in the province of Hubei in China. Italy was one of the most affected countries with many cases diagnosed already in February 2020 and a lockdown was declared on March 9th. Limited information has been reported with regard to the impact of the pandemic on chronic myeloid leukemia (CML) patients. Aims: To observe the temporal course of Covid-19 infection and the characteristics of positive patients. Methods: The Campus CML Italian group carried out a first survey on the management of CML patients during the lockdown. We launched a second survey during the pandemic phases 2 and 3, between May 2020 and January 2021. Results: We collected retrospective information on 8665 CML patients followed at 46 centers throughout the country. Within this cohort, we recorded 217 Covid-19-positive symptomatic patients (2.5%). Most patients (57%) were diagnosed as having Covid-19 infection between September 2020 and January 2021;30% were diagnosed in phase 1 (March-April 2020) and only 13% between May and August. Most of the positive patients were between 50 and 65 years (35%), while 26% had less than 50 years, 18.8% were between 65 and 75 years, and 11% had more than 75 years. A male prevalence was observed (73%). The median time from CML diagnosis to Covid-19 infection was 6 years (3 months-18 years). Fifty-six percent of patients presented concomitant comorbidities at the time of infection. When Covid-19 was diagnosed, 27% of patients were receiving imatinib, 26% nilotinib, 18% dasatinib, 8% ponatinib, 8% bosutinib, 2% asciminib, while 11% were not receive treatment. At the time of the infection, 74% of patients were in molecular remission, 6% in complete cytogenetic remission, 3% in partial cytogenetic remission, 6% in complete hematological response and 11% in treatment-free remission. At diagnosis, 28% of patients presented fever and respiratory symptoms, 13% cough, 10% isolated fever, 13% ageusia, 12% anosmia, 4% had more than 1 symptom, while 20% were completely asymptomatic. Twenty-one patients (9.6%) required hospitalization without the need of respiratory assistance, 18 (8.2%) were hospitalized for respiratory assistance, 8 (3.6%) were admitted to an ICU, while 150 patients (69%) were only quarantined. Twenty-three percent of patients discontinued TKI therapy during the infection. The source of contagion was familiar in 49% of patients, 18% due to work, 3% in healthcare professionals, whereas in 30% was not known. Twelve patients died due to Covid-19 infection with a mortality rate of 5.5% in the positive cohort and of 0.13% in the whole cohort. Five patients reported consequences post-infection: 1 patient reported a Guillan-Barrè syndrome, 1 patient a maculopapular rash, 1 patient a pulmonary fibrosis, 1 patient a bacterial endocarditis and 1 patient was diagnosed as having alterations of the microcirculation. Summary/Conclusion: This study reports the 1-year of data on the Covid- 19 infection in a specific hematological malignancy in the European country first hit by the pandemic. A longer follow-up is needed to further define the impact of Covid-19 infection sequelae in CML patients.
ABSTRACT
Introduction: The median age of CML patients failing a first-line TKI because of resistance or intolerance is higher than 60 years. Bosutinib (BOS), dasatinib (DAS) and nilotinib (NIL) have similar second-line efficacy, but in elderly patients DAS and NIL toxicity is more frequent and more clinically relevant. BOS safety profile may be an added value in this setting, but the approved initial dose of 500 mg OAD may be higher than necessary. Aims: All TKIs have been tested in CML patients at a fixed initial dose, with dose reductions in case of toxicity. On the contrary, the aim of our study was to evaluate the efficacy and the tolerability of low-dose second-line BOS in elderly CML patients, using the molecular response at given timepoints to increase the dose only in selected patients, thus finding the minimum effective dose. Methods: A prospective phase 2 single-arm multicenter study has been designed by the GIMEMA CML Working Party (NCT02810990). Study design: All patients started BOS 200 mg OAD for 2 weeks (ârun-inâ period), then the dose was increased to 300 mg OAD;after 3 months, patients with BCR-ABLIS transcript ≤ 1% continued 300 mg OAD, while in patients with transcript > 1% the dose is furtherly increased to 400 mg OAD, in absence of relevant toxicity. The primary endpoint was the rate of MR3 at 12 months. Key inclusion criteria: > 60 yrs old, chronic phase CML, intolerance or failure of any first-line TKI (2013 ELN criteria), absence of T315I or V299L mutation. Results: Sixty-three patients have been enrolled. Median age: 73 yrs (range 60-90). Reasons for switching to BOS: Intolerance 63%, resistance 37%. First-line TKI: Imatinib 83%, DAS 11%, NIL 6%. All patients reached at least 1-year observation. Due to the emergency situation caused by SARS CoV2 spread in Italy, few data are still missing, but final results will be presented onsite. Maximum BOS dose: 400 mg OAD, 19%;300 mg OAD, 76%;200 mg OAD, 5%. At baseline, 17% of patients were already in MR3;MR3 rates at 3, 6 and 12 months were 44%, 54% and 59%, respectively. The cumulative rate of patients achieving or maintaining a MR3 by 12 months was 67%;patients achieving MR4 or MR4.5 by 12 months were 44% and 24%, respectively. Overall, 30%, 29% and 8% of patients had 1 log, 2 logs or > 3 logs reduction from baseline BCR-ABLIS transcript level (67% of patients had a molecular improvement from baseline). Selected adverse events: Acute coronary syndromes, 4 patients;pericarditis, 2 patients;peripheral arterial thrombosis, 1 patient;no pleural effusions were observed. Events leading to permanent treatment discontinuation: 2 unrelated deaths, 7 adverse events, 4 unsatisfactory responses (without progressions), 1 second neoplasia. Fourty-nine patients are still on BOS at the last contact: 10% of them on 400 mg OAD, 61% on 300 mg OAD, 29% on 200 mg OAD. Conclusions: These results trial showed that in elderly patients intolerant to or failing a first-line TKI BOS may be highly effective and better tolerated at a dose lower than 500 mg OAD, namely at 300 mg OAD.