Cladribine Efficacy in a Patient with Hairy Cell Leukemia and Severe Renal Insufficiency.

BACKGROUND: Hairy cell leukemia commonly presents with pancytopenia, indolent course, and predisposition as infectious complications. Current first-line therapeutic options are purine analogues, particularly cladribine, with a high percentage of complete responses and durable remissions. However, their use is poorly investigated in patients affected by severe chronic renal insufficiency. CASE PRESENTATION: Here, we describe a case of HCL in a 68-year-old man affected by multiple comorbidities, including severe chronic renal failure. After a course of interferon-α, the patient received therapy with Cladribine every other week, obtaining a complete hematological remission and improvement of renal function. DISCUSSION: With a different soft schedule of cladribine, the patient was treated adequately, obtaining a complete remission. CONCLUSION: Cladribine can be administered with caution, even in patients with renal failure, with good results.

Prospective monitoring of chronic myeloid leukemia patients from the time of TKI discontinuation: the fate of peripheral blood CD26+ leukemia stem cells.

Introduction: In chronic myeloid leukemia (CML), about half of the patients achieving a deep and stable molecular response with tyrosine kinase inhibitors (TKIs) may discontinue TKI treatment without disease recurrence. As such, treatment-free remission (TFR) has become an ambitious goal of treatment. Given the evidence that deepness and duration of molecular response are necessary but not sufficient requisites for a successful TFR, additional biological criteria are needed to identify CML patients suitable for efficacious discontinuation. Leukemia stem cells (LSCs) are supposed to be the reservoir of the disease. Previously, we demonstrated that residual circulating CD34+/CD38-/CD26+ LSCs were still detectable in a consistent number of CML patients during TFR. Methods: CML LSCs could be easily identified by flow-cytometry as they express the CD34+/CD38-/CD26+ phenotype. In this study, we explored the role of these cells and their correlation with molecular response in a cohort of 109 consecutive chronic phase CML patients prospectively monitored from the time of TKI discontinuation. Results: After a median observation time of 33 months from TKI discontinuation, 38/109 (35%) patients failed TFR after a median time of 4 months, while 71/109 (65%) patients are still in TFR. At TKI discontinuation, peripheral blood CD26+LSCs were undetectable in 48/109 (44%) patients and detectable in 61/109 (56%). No statistically significant correlation between detectable/undetectable CD26+LSCs and the rate of TFR loss was found (p = 0.616). The incidence of TFR loss based on the type of TKI treatment was statistically significant for imatinib treatment compared to that of nilotinib (p = 0.039). Exploring the behavior of CD26+LSCs during TFR, we observed fluctuating values that were very variable between patients, and they were not predictive of TFR loss. Discussion: Up to date, our results confirm that CD26+LSCs are detectable at the time of TKI discontinuation and during TFR. Moreover, at least for the observation median time of the study, the persistence of "fluctuating" values of residual CD26+LSCs does not hamper the possibility to maintain a stable TFR. On the contrary, even patients discontinuing TKI with undetectable CD26+LSCs could undergo TFR loss. Our results suggest that factors other than residual LSCs "burden" playing an active role in controlling disease recurrence. Additional studies evaluating CD26+LSCs' ability to modulate the immune system and their interaction in CML patients with very long stable TFR are ongoing.

Anti-BCMA novel therapies for multiple myeloma.

Recent advances in multiple myeloma therapy have increased the depth of response and ultimately survivals; however, the prognosis remains poor. The BCMA antigen is highly expressed in myeloma cells, thus representing a target for novel therapies. Several agents that target BCMA through different mechanisms, including bispecific T cell engagers drug conjugated to antibody and CAR-T cells, are now available or under development. Immunotherapies targeting BCMA have shown good results in efficacy and safety in multiple myeloma patients previously treated with several lines of therapy. This review will discuss the recent development of anti-BCMA targeted treatments in myeloma, with a special focus on currently available agents.

Functional Imaging in the Evaluation of Treatment Response in Multiple Myeloma: The Role of PET-CT and MRI.

Bone disease is among the defining characteristics of symptomatic Multiple Myeloma (MM). Imaging techniques such as fluorodeoxyglucose positron emission tomography-computed tomography (FDG PET/CT) and magnetic resonance imaging (MRI) can identify plasma cell proliferation and quantify disease activity. This function renders these imaging tools as suitable not only for diagnosis, but also for the assessment of bone disease after treatment of MM patients. The aim of this article is to review FDG PET/CT and MRI and their applications, with a focus on their role in treatment response evaluation. MRI emerges as the technique with the highest sensitivity in lesions' detection and PET/CT as the technique with a major impact on prognosis. Their comparison yields different results concerning the best tool to evaluate treatment response. The inhomogeneity of the data suggests the need to address limitations related to these tools with the employment of new techniques and the potential for a complementary use of both PET/CT and MRI to refine the sensitivity and achieve the standards for minimal residual disease (MRD) evaluation.

The third dose of mRNA SARS-CoV-2 vaccines enhances the spike-specific antibody and memory B cell response in myelofibrosis patients.

Vaccination against SARS-CoV-2 using mRNA-based vaccines has been highly recommended for fragile subjects, including myelofibrosis patients (MF). Available data on the immune responsiveness of MF patients to mRNA SARS-CoV-2 vaccination, and the impact of the therapy with the JAK inhibitor ruxolitinib, are still fragmented. Here, we profile the spike-specific IgG and memory B-cell response in MF patients, treated or not with ruxolitinib, after the second and the third dose of SARS-CoV-2 BNT162b2 (BioNTech) and mRNA-1273 (Moderna) vaccines. Plasma and peripheral blood mononuclear cells samples were collected before vaccination, post the second and the third doses and tested for spike-specific antibodies, ACE2/RBD antibody inhibition binding activity and spike-specific B cells. The third vaccine dose significantly increased the spike-specific IgG titers in both ruxolitinib-treated and untreated patients, and strongly enhanced the percentage of subjects with antibodies capable of in vitro blocking ACE2/RBD interaction, from 50% up to 80%. While a very low frequency of spike-specific B cells was measured in blood 7 days after the second vaccination dose, a strong and significant increase was elicited by the third dose administration, generating a B cell response similar to the one detected in healthy controls. Despite the overall positive impact of the third dose in MF patients, two patients that were under active concomitant immunosuppressive treatment at the time of vaccination, and a patient that received lymphodepleting therapies in the past, remained low responders. The third mRNA vaccine dose strongly increases the SARS-CoV-2 specific humoral and B cell responses in MF patients, promoting a reactivation of the immune response similar to the one observed in healthy controls.

Central Nervous System Myeloma and Unusual Extramedullary Localizations: Real Life Practical Guidance.

Central nervous system localization of multiple myeloma (CNS-MM) accounts for about 1% of all MM during disease course or even rarer at diagnosis. A difference in the origin, i.e., osteodural or primary dural vs leptomeningeal/intraparenchymal, seems to define two distinct types of intracranial myeloma, with different clinical behavior. CNS-MM may occur also as a presentation of MM. Treatment is still unsatisfactory and many treatments have been reported: chemotherapy, intrathecal therapy, and radiotherapy, with dismal prognosis. Other sites of myeloma localization could be also of interest and deserve description. Because of the rarity and aggressiveness of the disease clinicians are often doubtful on how to treat it since there is no general agreement. Moreover, recent drugs such as the anti CD38 monoclonal antibody, immunomodulatory drugs, and proteasome inhibitors have changed the treatment of patients with MM with a significant improvement in overall response and survival. The role of novel agents in CNS MM management and unusual presentations will be discussed as well as the potential role of other new immunomodulatory drugs and proteasome inhibitors that seem to cross the blood-brain barrier. The purpose of this review is to increase awareness of the clinical unusual presentation and neuroradiological findings, give practical diagnostic advice and treatment options algorithm.

Therapeutic Management of Patients with FLT3 + Acute Myeloid Leukemia: Case Reports and Focus on Gilteritinib Monotherapy.

Acute myeloid leukemia is a malignant disorder of the bone marrow, characterized by differentiation, clonal expansion, and uncontrolled proliferation of malignant myeloid progenitor cells and by several molecular and genetic abnormalities. A mutation of FMS-like tyrosine kinase 3 gene can be observed in about one-third of cases of acute myeloid leukemia. Two FLT3 inhibitors are actually approved for FLT3 mutated acute myeloid leukemia: midostaurin, a multikinase first generation inhibitor with lower affinity for FLT3 binding, and gilteritinib fumarate, a potent second-generation inhibitor of both FLT3-ITD and TKD. Gilteritinib is a new effective and well-tolerated drug for patients with relapsing or refractory FLT3-positive acute myeloid leukemia. Thanks to its efficacy, low toxicity, its good manageability (oral formulation), this drug is suitable for all the patients, including elderly frail patient with concomitant therapies or pre-existing or underlying diseases, and can be used also in the outpatient setting, reducing risks and costs related to the hospitalization. We report and discuss seven cases of different patients with FLT3 positive acute myeloid leukemia successfully managed with gilteritinib in the real clinical practice.

Daratumumab in AL Amyloidosis: A Real-Life Experience of the "RTM" (Regional Tuscan Myeloma Network).

Systemic amyloidosis arises from monoclonal CD38+ plasma cells that produce misfolded immunoglobulin light chains, which form amyloid fibrils that are deposited into different tissues, leading to organ damage. Daratumumab is a human IgG/k monoclonal antibody that targets CD38, a glycoprotein uniformly expressed on human plasma cells. Daratumumab has been utilized in recent years with unprecedented responses in multiple myeloma. In patients with relapsed or refractory AL amyloidosis, daratumumab has shown promising efficacy in terms of hematologic responses and improvement in organ function. Here, we report real-life treatment with Daratumumab in 33 AL amyloidosis patients treated within the Regional Tuscan Myeloma network at 5 centers with associated MGUS or SMM (n = 15) or symptomatic MM (n = 18). Patients were treated at relapsed/refractory disease stages (n = 29) with a median of one previous line of therapy or at diagnosis (n = 4). Daratumumab showed good efficacy, representing 60% of good hematological responses and 50% of organ responses in a real-life population of patients with an acceptable toxicity profile.

Pro-Inflammatory and Pro-Oxidative Changes During Nilotinib Treatment in CML Patients: Results of a Prospective Multicenter Front-Line TKIs Study (KIARO Study).

Tyrosine kinase inhibitors (TKI) may offer a normal life expectancy to Chronic Myeloid Leukemia (CML) patients. However, a higher than expected incidence of arterial occlusive events (AOEs) was observed during treatment with nilotinib. We previously showed an "inflammatory status" during nilotinib that may explain the increased incidence of AOEs. Thus, we conducted this prospective KIARO study involving 186 CML patients (89 imatinib, 59 nilotinib, 38 dasatinib). Interleukin 6 (IL6), interleukin 10 (IL10), Tumor Necrosis Factor-α (TNFα), oxLDL, and high-sensitivity C-reactive protein (hs-CRP) plasma levels were measured at diagnosis and during treatment, with the aim to investigate changes in the inflammatory status favoring AOEs of each patient. Clinical and biochemical pro-atherothrombotic profiles and the 10-year SCORE chart were also evaluated. We showed a pro-inflammatory/pro-oxidative milieu increasing along treatment with nilotinib compared with imatinib or dasatinib, as demonstrated by higher hs-CRP and oxLDL levels and increased IL6/IL10 and TNFα/IL10 ratios only in nilotinib cohort. After median follow-up of 23.3 months starting from TKI, 10/186 patients (5.4%) suffered an AOE. Approximately 5/10 (50%) AOEs occurred during nilotinib treatment despite a lower 10-year SCORE and a lower median age in this subgroup. A longer follow-up is needed to further confirm the active role of nilotinib in AOEs pathogenesis.

The Slower Antibody Response in Myelofibrosis Patients after Two Doses of mRNA SARS-CoV-2 Vaccine Calls for a Third Dose.

Immunization with mRNA SARS-CoV-2 vaccines has been highly recommended and prioritized in fragile subjects, including patients with myelofibrosis (MF). Available data on the vaccine immune response developed by MF patients and the impact of ruxolitinib treatment are still too fragmented to support an informed decision on a third dose for this category of subjects. Here, we show that 76% of MF patients develop spike-specific IgG after the second mRNA SARS-CoV-2 vaccine dose, but the response has a slower kinetics compared to healthy subjects, suggesting a reduced capability of their immune system to promptly react to vaccination. A reduced ACE2/RBD binding inhibition activity of spike-specific antibodies was also observed, especially in ruxolitinib-treated patients. Our results, showing slow kinetics of antibody responses in MF patients following vaccination with mRNA SARS-CoV-2 vaccines, support the need for a third vaccine dose.

First reported case of secondary mixed phenotype acute leukemia after multiple myeloma.

In recent years the outcome of patients with multiple myeloma (MM) has significantly improved, due to new drugs. However, some agents, i.e. the alkylating drug melphalan, can be associated with an increased incidence of secondary malignancies. Myelodysplastic syndromes and acute myeloid leukemia are reported in the literature, and rarely acute lymphoblastic leukemia. Here we describe a unique case of a 56-years old female patient affected by MM since 2015 in complete remission after autologous stem cell transplant and in lenalidomide maintenance, who developed 2 years later mixed phenotype acute leukemia (MPAL). The patient, refractory to both lymphoblastic and myeloid acute leukemia regimens, achieved complete remission with bi-specific anti-CD19/anti-CD3 monoclonal antibody blinatumomab and with hypomethylating agent azacytidine plus the BCL-2 inhibitor venetoclax. She then underwent hematopoietic stem cell transplantation from HLA-identical sibling donor and she is still in complete remission after 9 months. To the best of our knowledge, there are no cases in the literature describing MPAL after autologous transplant for MM. Our patient was treated with blinatumomab and venetoclax and achieved complete remission 9 months from allogeneic transplant. The mechanism underlying the development of MPAL is not completely understood and therapies are still lacking. In this context the combination of blinatumomab, azacytidine and venetoclax successfully used in this patient may provide food for thought for further studies in this rare setting of patients.

Efficacy and safety of eltrombopag during conception and first trimester of pregnancy in a case of refractory severe immune thrombocytopenia.

: Immune thrombocytopenia (ITP) is a relatively frequent cause of thrombocytopenia during pregnancy. Thrombopoietin receptor agonists (TPO-RAs) are the most recent drugs approved for second-line treatment of ITP. Limited data are available about their use in pregnancy with only a few published cases; yet no data exist about their effect when administered only during conception and first trimester of gestation. We describe the case of a woman with refractory ITP who took eltrombopag during conception and first trimester of pregnancy. No fetal or maternal complications were reported. Moreover, the patient remained in complete response after delivery despite therapy discontinuation. The analysis of this case and the revision of the available literature suggest that the use of TPO-RAs, thanks to their short time to response, may be effective and feasible during the first trimester of pregnancy, even if not yet recommended by current guidelines.

Long-Term Safety of Rapid Daratumumab Infusions in Multiple Myeloma Patients.

Multiple myeloma survival has significantly improved in recent years, due to novel agents that are available for treatment. The anti-CD38 monoclonal antibody Daratumumab is particularly efficient for patients with relapse/refractory disease, and many studies have shown its unprecedented efficacy also as a first treatment. However, to avoid the incidence of infusion reactions, long infusion schedules of 8 h at first dose and 4 h in the following doses are required, which can reduce the compliance of patients and health care professionals. A reduced infusion time of 90 min has been reported previously, but data are missing on the prolonged safety of this over time as well as the efficacy of this approach. In this work, we investigate the safety of 484 rapid Daratumumab infusions given early after the second dose over a 22 months period in 39 myeloma patients.

Real-world experience with decitabine as a first-line treatment in 306 elderly acute myeloid leukaemia patients unfit for intensive chemotherapy.

Despite widespread use of decitabine to treat acute myeloid leukaemia (AML), data on its effectiveness and safety in the real-world setting are scanty. Thus, to analyze the performance of decitabine in clinical practice, we pooled together patient-level data of three multicentric observational studies conducted since 2013 throughout Italy, including 306 elderly AML patients (median age 75 years), unfit for intensive chemotherapy, treated with first-line decitabine therapy at the registered schedule of 20 mg/m2 /iv daily for 5 days every 4 weeks. Overall response rate (ORR), overall survival (OS) curves, and multivariate hazard ratios (HRs) of all-cause mortality were computed. Overall, 1940 cycles of therapy were administered (median, 5 cycles/patient). A total of 148 subjects were responders and, therefore, ORR was 48.4%. Seventy-one patients (23.2%) had complete remission, 32 (10.5%) had partial remission, and 45 (14.7%) had haematologic improvement. Median OS was 11.6 months for patients with favourable-intermediate cytogenetic risk and 7.9 months for those with adverse cytogenetic risk. Median relapse-free survival after CR was 10.9 months (95% confidence interval [CI]: 8.7-16.0). In multivariate analysis, mortality was higher in patients with adverse cytogenetic risk (HR=1.58; 95% CI: 1.13-2.21) and increased continuously with white blood cell (WBC) count (HR=1.12; 95% CI: 1.06-1.18). A total of 183 infectious adverse events occurred in 136 patients mainly (>90%) within the first five cycles of therapy. This pooled analysis of clinical care studies confirmed, outside of clinical trials, the effectiveness of decitabine as first-line therapy for AML in elderly patients unfit for intensive chemotherapy. An adverse cytogenetic profile and a higher WBC count at diagnosis were, in this real life setting, unfavourable predictors of survival.