Are small lymphocytic lymphoma and chronic lymphocytic leukemia the same disease? The unsolved dilemma.

The management of small lymphocytic lymphoma (SLL) as chronic lymphocytic leukemia (CLL) or an indolent non-Hodgkin lymphoma is highly debated. In this single-center, real-life study, 38 SLL patients managed between 2008 and 2022 were evaluated. Overall, 26/38 cases (68.4%) needed treatment and all but one received CLL concordant therapy, including BR (9/38 cases), fludarabine, cyclophosphamide, rituximab (5/38 cases), rituximab and chlorambucil (4/38 cases), BTK inhibitors (7/38 cases) and steroid (1 case with immune thrombocytopenia). Patients treated between 2008 and 2018 were more likely to receive chemoimmunotherapy compared to patients treated in 2019-2022, that were more likely to receive BTK inhibitors. The median PFS was 54 months and 3-y PFS was 58%, while the median OS was not reached, with a 3-y OS of 84%. We confirm a wide heterogeneity in SLL management and we suggest prospective studies are needed to improve the knowledge of its biology and harmonize its treatment.

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.

Minimal Residual Disease Detection at RNA and Leukemic Stem Cell (LSC) Levels: Comparison of RT-qPCR, d-PCR and CD26+ Stem Cell Measurements in Chronic Myeloid Leukemia (CML) Patients in Deep Molecular Response (DMR).

A Deep Molecular Response (DMR), defined as a BCR::ABL1 transcript at levels ≤ 0.01% by RT-qPCR, is the prerequisite for the successful interruption of treatment among patients with Chronic Myeloid Leukemia (CML). However, approximately 50% of patients in Treatment-Free Remission (TFR) studies had to resume therapy after their BCR::ABL1 transcript levels rose above the 0.1% threshold. To improve transcript detection sensitivity and accuracy, transcript levels can be analyzed using digital PCR (dPCR). dPCR increases BCR::ABL1 transcript detection sensitivity 10-100 fold; however, its ability to better select successful TFR patients remains unclear. Beyond the role of the immune system, relapses may be due to the presence of residual leukemic stem cells (LSCs) that are transcriptionally silent. Flow cytometry can be used to identify and quantify circulating bone marrow Ph+ LSCs CD34+/CD38- co-expressing CD26 (dipeptidylpeptidase-IV). To date, the significance of circulating Ph+ LSCs in TFR is unclear. The aim of this work is to compare and examine the values obtained using the three different methods of detecting minimal residual disease (MRD) in CML at RNA (RT-qPCR and dPCR) and LSC (flowcytometry) levels among patients in TFR or exhibiting a DMR. The twenty-seven patients enrolled received treatment with either imatinib (12), dasatinib (6), nilotinib (7), bosutinib (1), or interferon (1). Twelve patients were in TFR, while the rest exhibited a DMR. The TFR patients had stopped therapy for less than 1 year (3), <3 years (2), 6 years (6), and 17 years (1). Blood samples were collected and tested using the three methods at the same time. Both d-PCR and LSCs showed higher sensitivity than RT-qPCR, exhibiting positive results in samples that were undetectable using RT-qPCR (17/27). None of the patients tested negative with d-PCR; however, 23/27 were under the threshold of 0.468 copies/µL, corresponding to a stable DMR. The results were divided into quartiles, and the lowest quartiles defined the lowest MRD. These data were strongly correlated in 15/27 patients, corresponding to almost half of the TFR patients. Indeed, the TFR patients, some lasting up to 17 years, corresponded to the lowest detectable DMR categories. To the best of our knowledge, this is the first attempt to analyze and compare DMRs in a CML population using standard (RT-qPCR) and highly sensitive (dPCR and LSCs) methods.

The prognostic role of gene polymorphisms in patients with indolent non-Hodgkin lymphomas and mantle-cell lymphoma receiving bendamustine and rituximab: results of the 5-year follow-up study.

The variability in disease outcome for indolent non-Hodgkin lymphomas (iNHL) and mantle-cell lymphoma (MCL) could be related to single nucleotide polymorphisms (SNPs) in genes that affect immune and inflammatory response. We investigated SNPs that could have a prognostic role for patients receiving bendamustine and rituximab (BR). All samples were genotyped for the IL-2 (rs2069762), IL-10 (rs1800890, rs10494879), VEGFA (rs3025039), IL-8 (rs4073), CFH (rs1065489) and MTHFR (rs1801131) SNPs by allelic discrimination assays using TaqMan SNP Genotyping Assays. We report a long-term follow-up analysis of 79 iNHL and MCL patients that received BR. Overall response rate was 97.5% (CR rate 70.9%). After a median follow-up of 63 months, median PFS and OS were not reached. We report a significant association between SNP in IL-2 (rs2069762) and reduced PFS and OS (p<.0001). We suggest a role for cytokine SNPs in disease outcome, while SNPs seem not related to long-term toxicity or secondary malignancies.

Tumor-Associated Macrophages in Multiple Myeloma: Key Role in Disease Biology and Potential Therapeutic Implications.

Multiple myeloma (MM) is characterized by multiple relapse and, despite the introduction of novel therapies, the disease becomes ultimately drug-resistant. The tumor microenvironment (TME) within the bone marrow niche includes dendritic cells, T-cytotoxic, T-helper, reactive B-lymphoid cells and macrophages, with a complex cross-talk between these cells and the MM tumor cells. Tumor-associated macrophages (TAM) have an important role in the MM pathogenesis, since they could promote plasma cells proliferation and angiogenesis, further supporting MM immune evasion and progression. TAM are polarized towards M1 (classically activated, antitumor activity) and M2 (alternatively activated, pro-tumor activity) subtypes. Many studies demonstrated a correlation between TAM, disease progression, drug-resistance and reduced survival in lymphoproliferative neoplasms, including MM. MM plasma cells in vitro could favor an M2 TAM polarization. Moreover, a possible correlation between the pro-tumor effect of M2 TAM and a reduced sensitivity to proteasome inhibitors and immunomodulatory drugs was hypothesized. Several clinical studies confirmed CD68/CD163 double-positive M2 TAM were associated with increased microvessel density, chemoresistance and reduced survival, independently of the MM stage. This review provided an overview of the biology and clinical relevance of TAM in MM, as well as a comprehensive evaluation of a potential TAM-targeted immunotherapy.

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.

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.

Drug resistance and minimal residual disease in multiple myeloma.

Great progress has been made in improving survival in multiple myeloma (MM) patients over the last 30 years. New drugs have been introduced and complete responses are frequently seen. However, the majority of MM patients do experience a relapse at a variable time after treatment, and ultimately the disease becomes drug-resistant following therapies. Recently, minimal residual disease (MRD) detection has been introduced in clinical trials utilizing novel therapeutic agents to measure the depth of response. MRD can be considered as a surrogate for both progression-free and overall survival. In this perspective, the persistence of a residual therapy-resistant myeloma plasma cell clone can be associated with inferior survivals. The present review gives an overview of drug resistance in MM, i.e., mutation of ß5 subunit of the proteasome; upregulation of pumps of efflux; heat shock protein induction for proteasome inhibitors; downregulation of CRBN expression; deregulation of IRF4 expression; mutation of CRBN, IKZF1, and IKZF3 for immunomodulatory drugs and decreased target expression; complement protein increase; sBCMA increase; and BCMA down expression for monoclonal antibodies. Multicolor flow cytometry, or next-generation flow, and next-generation sequencing are currently the techniques available to measure MRD with sensitivity at 10-5. Sustained MRD negativity is related to prolonged survival, and it is evaluated in all recent clinical trials as a surrogate of drug efficacy.

Long-term CR Multiple Myeloma Patients Show Cured or MGUS-like Minimal Residual Disease Pattern by Next Generation Flow.

BACKGROUND: In the era of novel agents, many multiple myeloma patients can achieve a complete remission, but most of them relapse, and minimal residual disease detection can play a crucial role. Next-generation flow (NGF) can detect monoclonal plasma cells with a sensitivity of 10-6. Little is known about long-term remission patients (> 2 years) and in particular, if more sensitive techniques such as NGF can still detect minimal disease in those patients. OBJECTIVE: Aim of the study was to analyze patients with MM in response to NGF at > 2 years of sustained remission after several treatments. METHODS: MRD was studied by NGF in bone marrow aspirates according to Euroflow Consortium indications. RESULTS: 62 patients with sustained CR at >2 years were studied, MRD+ status was detected at a threshold cut-off of 10-6 in 32/62 (52%); 4/15 (27%) patients were MRD positive at >5 years of remission and they displayed a prevalence of normal vs abnormal monoclonal plasma cell immune-phenotype (MGUS-like). CONCLUSION: NGF is a powerful technique to detect MRD. Myeloma patients in prolonged sustained complete remission can show in high percentage an MRD negative status or MGUS like.

Overview of Anti-SARS-CoV-2 Immune Response Six Months after BNT162b2 mRNA Vaccine.

BACKGROUND: We have designed a prospective study aiming to monitor the immune response in 178 health care workers six months after BNT162b2 mRNA vaccination. METHODS: The humoral immune response of all subjects was evaluated by chemiluminescence (CMIA); in 60 serum samples, a live virus-based neutralization assay was also tested. Moreover, 6 months after vaccination, B- and T-cell subsets from 20 subjects were observed by FACS analysis after restimulation with the trimeric SARS-CoV-2 Spike protein as an antigen, thus mimicking reinfection in vitro. RESULTS: A significant decrease of circulating IgG levels and neutralizing antibodies over time were observed. Moreover, six months after vaccination, a variable T-cell immune response after in vitro antigen stimulation of PBMC was observed. On the contrary, the analysis of B-cell response showed a shift from unswitched to switched memory B-cells and an increase of Th17 cells. CONCLUSIONS: Although the variability of the CD4+ and CD8+ immune response and an antibody decline was observed among vaccinated subjects, the increase of switched memory B-cells and Th17 cells, correlating with the presence of neutralizing antibodies, opened the debate on the correct timing of vaccination.

CD26/DPP-4 in Chronic Myeloid Leukemia.

CD26 expression is altered in many solid tumors and hematological malignancies. Recently, it has been demonstrated that it is a specific marker expressed on LSCs of CML, both in BM and PB samples, and absent on CD34+/CD38- stem cells in normal subjects or on LSCs of other myeloid neoplasms. CD26+ LSCs have been detected by flow-cytometry assays in all PB samples of Chronic-Phase CML patients evaluated at diagnosis. Additionally, it has been demonstrated that most CML patients undergoing Tyrosine Kinase Inhibitors (TKIs) treatment still harbored circulating measurable residual CD26+ LSCs, even when displaying a consistent deep molecular response without any significant association among the amounts of BCR-ABL transcript and CD26+ LSCs. Preliminary data of our Italian prospective multicenter study showed that CML patients with a poorer response presented with a higher number of CD26+ LSCs at diagnosis. These data confirmed that CD26 is a specific marker of CML and suggest that it could be considered for the monitoring of therapeutic responses.

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.

A novel class of oxazepine-based anti-cancer agents induces cell death in primary human CLL cells and efficiently reduces tumor growth in Eµ-TCL1 mice through the JNK/STAT4/p66Shc axis.

Survival and expansion of malignant B cells in chronic lymphocytic leukemia (CLL) are highly dependent both on intrinsic defects in the apoptotic machinery and on the interactions with cells and soluble factors in the lymphoid microenvironment. The adaptor protein p66Shc is a negative regulator of antigen receptor signaling, chemotaxis and apoptosis whose loss in CLL B cells contributes to their extended survival and poor prognosis. Hence, the identification of compounds that restore p66Shc expression and function in malignant B cells may pave the way to a new therapeutic approach for CLL. Here we show that a novel oxazepine-based compound (OBC-1) restores p66Shc expression in primary human CLL cells by promoting JNK-dependent STAT4 activation without affecting normal B cells. Moreover, we demonstrate that the potent pro-apoptotic activity of OBC-1 in human leukemic cells directly correlates with p66Shc expression levels and is abrogated when p66Shc is genetically deleted. Preclinical testing of OBC-1 and the novel analogue OBC-2 in Eµ-TCL1 tumor-bearing mice resulted in a significantly longer overall survival and a reduction of the tumor burden in the spleen and peritoneum. Interestingly, OBCs promote leukemic cell mobilization from the spleen to the blood, which correlates with upregulation of sphingosine-1-phosphate receptor expression. In summary, our work identifies OBCs as a promising class of compounds that, by boosting p66Shc expression through the activation of the JNK/STAT4 pathway, display dual therapeutic effects for CLL intervention, namely the ability to mobilize cells from secondary lymphoid organs and a potent pro-apoptotic activity against circulating leukemic cells.

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.

The Role of Tumor-Associated Macrophages in Hematologic Malignancies.

The tumor microenvironment includes dendritic cells, T-cytotoxic, T-helper, reactive B-lymphoid cells and macrophages; these reactive cells could interplay with malignant cells and promote tumor growth and survival. Among its cellular components, tumor-associated macrophages (TAM) represent a component of the innate immune system and play an important role, especially in hematologic malignancies. Depending on the stimuli that trigger their activation, TAM are polarized towards form M1, contributing to antitumor responses, or M2, associated with tumor progression. Many studies demonstrated a correlation between TAM, disease progression and the patient's outcome in lymphoproliferative neoplasms, such as Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL), even if with conflicting results. A critical hurdle to overcome is surely represented by the heterogeneity in the choice of the optimal markers and methods used for TAM analysis (gene-expression profile vs. immunohistochemistry, CD163vs. CD68vs. CD163/CD68 double-positive cells). TAM have been recently linked to the development and progression of multiple myeloma and leukemia, with a critical role in the homing of malignant cells, drug resistance, immune suppression and angiogenesis. As such, this review will summarize the role of TAM in different hematologic malignancies, focusing on the complex interplay between TAM and tumor cells, the prognostic value of TAM and the possible TAM-targeted therapeutic strategies.

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.

Low-density lipoprotein (LDL) levels and risk of arterial occlusive events in chronic myeloid leukemia patients treated with nilotinib.

Recommendations for dyslipidemia management aimed at reducing arterial occlusive events (AOEs) have been recently published. So far, no data have been reported on the management of dyslipidemia in chronic myeloid leukemia (CML) patients treated with nilotinib. We investigated 369 CML adult patients, stratified according to the new Systematic Coronary Risk Evaluation (SCORE) scoring system. Plasma levels of cholesterol, HDL, LDL, and triglycerides were measured prior to the start of nilotinib and after 3, 6, and 12 months. The 5-year cumulative incidence of AOEs was 15.9%. Patients with cholesterol levels > 200 mg/dL and LDL > 70 mg/dL 3 months after treatment showed a significantly higher incidence of AOEs (21.9 ± 4.6% vs 6.2 ± 2.5, P = 0.003). Patients belonging to the high and very high SCORE risk group showed a significant increase of AOEs (34.4 ± 6% vs 10 ± 2.1%, P < 0.001). In multivariate analysis, both high cholesterol and LDL levels and a high and very high SCORE risk remained significantly associated with the risk of AOEs (P = 0.008; HR = 3.5; 95% CI = 1.4-8.7 and P < 0.001; HR = 4.4; 95% CI = 2-9.8, respectively). Overall, 78 patients (21.1%) presented dyslipidemia at the time of CML diagnosis and 88 (23.3%) after starting nilotinib, but only 26 of them (29.5%) were treated with statins.Low LDL and cholesterol plasma levels are associated with a significant lower risk of AOEs in CML patients treated with nilotinib in the real life.

Fludarabine, High-Dose Cytarabine and Idarubicin-Based Induction May Overcome the Negative Prognostic Impact of FLT3-ITD in NPM1 Mutated AML, Irrespectively of FLT3-ITD Allelic Burden.

The mutations of NPM1 and FLT3-ITD represent the most frequent genetic aberration in acute myeloid leukemia. Indeed, the presence of an NPM1 mutation reduces the negative prognostic impact of FLT3-ITD in patients treated with conventional "3+7" induction. However, little information is available on their prognostic role with intensified regimens. Here, we investigated the efficacy of a fludarabine, high-dose cytarabine and idarubicin induction (FLAI) in 149 consecutive fit AML patients (median age 52) carrying the NPM1 and/or FLT3-ITD mutation, treated from 2008 to 2018. One-hundred-and-twenty-nine patients achieved CR (86.6%). After a median follow up of 68 months, 3-year overall survival was 58.6%. Multivariate analysis disclosed that both NPM1mut (p < 0.05) and ELN 2017 risk score (p < 0.05) were significant predictors of survival. NPM1-mutated patients had a favorable outcome, with no significant differences between patients with or without concomitant FLT3-ITD (p = 0.372), irrespective of FLT3-ITD allelic burden. Moreover, in landmark analysis, performing allogeneic transplantation (HSCT) in first CR proved to be beneficial only in ELN 2017 high-risk patients. Our data indicate that FLAI exerts a strong anti-leukemic effect in younger AML patients with NPM1mut and question the role of HSCT in 1st CR in NPM1mut patients with concomitant FLT3-ITD.

Venetoclax in association with decitabine as effective bridge to transplant in a case of relapsed early T-cell lymphoblastic leukemia.

A case of an early-relapsed high-risk T-ALL with high BCL-2 expression on leukemic blasts was successfully treated with decitabine and venetoclax, achieving a CR. We suggest decitabine and venetoclax should be synergistic in BCL2-positive ALL.