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Background: Anaplastic lymphoma kinase (ALK) plays a role in the development of lymphoma, lung cancer and neuroblastoma. While tyrosine kinase inhibitors (TKIs) have improved treatment outcomes, relapse remains a challenge due to on-target mutations and off-target resistance mechanisms. ALK-positive (ALK+) tumors can evade the immune system, partly through tumor-associated macrophages (TAMs) that facilitate immune escape. Cancer cells use "don't eat me" signals (DEMs), such as CD47, to resist TAMs-mediated phagocytosis. TKIs may upregulate pro-phagocytic stimuli (i.e., calreticulin, CALR), suggesting a potential therapeutic benefit in combining TKIs with an anti-CD47 monoclonal antibody (mAb). However, the impact of this combination on both TKIs-sensitive and resistant ALK+ tumors requires further investigation. Methods: A panel of TKIs-sensitive and resistant ALK+ cancer subtypes was assessed for CALR and CD47 expression over time using flow cytometry. Flow cytometry co-culture and fluorescent microscopy assays were employed to evaluate phagocytosis under various treatment conditions. Results: ALK inhibitors increased CALR expression in both TKIs-sensitive and off-target resistant ALK+ cancer cells. Prolonged TKIs exposure also led to CD47 upregulation. The combination of ALK inhibitors and anti-CD47 mAb significantly enhanced phagocytosis compared to anti-CD47 alone, as confirmed by flow cytometry and fluorescent microscopy. Conclusions: Anti-CD47 mAb can quench DEMs while exposing pro-phagocytic signals, promoting tumor cell phagocytosis. ALK inhibitors induced immunogenic cell damage by upregulating CALR in both sensitive and off-target resistant tumors. Continuous TKIs exposure in off-target resistant settings also resulted in the upregulation of CD47 over time. Combining TKIs with a CD47 blockade may offer therapeutic benefits in ALK+ cancers, especially in overcoming off-target resistance where TKIs alone are less effective. [ABSTRACT FROM AUTHOR] more...

Summary: In a first‐of‐its‐kind study, we assessed the capabilities of large language models (LLMs) in making complex decisions in haematopoietic stem cell transplantation. The evaluation was conducted not only for Generative Pre‐trained Transformer 4 (GPT‐4) but also conducted on other artificial intelligence models: PaLm 2 and Llama‐2. Using detailed haematological histories that include both clinical, molecular and donor data, we conducted a triple‐blind survey to compare LLMs to haematology residents. We found that residents significantly outperformed LLMs (p = 0.02), particularly in transplant eligibility assessment (p = 0.01). Our triple‐blind methodology aimed to mitigate potential biases in evaluating LLMs and revealed both their promise and limitations in deciphering complex haematological clinical scenarios. [ABSTRACT FROM AUTHOR] more...

Objectives: Erythropoiesis‐stimulating agents (ESA) have an established role in treating anemia in hematological malignancies. However, their role, particularly biosimilar ESA (B‐ESA), in myelofibrosis (MF) is not well established. Methods: This study retrospectively collected data on 96 MF patients treated with B‐ESA (alpha/zeta) for the management of anemia to assess safety, efficacy (anemia response [AR]), and survival. Results: Seventy‐seven patients (80%) obtained AR. The median time to AR was 2.5 months. In multivariate analysis, significant predictive factors of AR were transfusion independency (p =.006) and ferritin levels <200 ng/ml (p =.009) at baseline. After a median follow‐up of 43.8 months from diagnosis, 38 patients (39%) died, 11 (28.9%) from leukemic evolution. Only two patients (2.5%) stopped B‐ESA for toxicity. The 24‐month survival was significantly affected by response to B‐ESA (70.8% in AR vs. 55.3% in non‐responder patients, p =.016). In multivariate analysis, age ≤ 70 years (p =.029) and Hb > 8.5 g/dl (p =.047) at baseline were significantly associated with improved survival, with a trend for longer survival in AR patients (p =.06). Conclusions: B‐ESA seems to be an effective and well‐tolerated option for anemia treatment in the MF setting. This strategy deserves further clinical investigation. [ABSTRACT FROM AUTHOR] more...

Background: Induction with daratumumab-based regimens followed by autologous stem cell transplantation is the current standard for newly diagnosed multiple myeloma (NDMM) patients eligible for intensive chemotherapy. However, concerns emerged regarding potential negative effects following daratumumab-based treatment on CD34+ mobilization. We here compared CD34+ mobilization and clonogenic potential between daratumumab and non-daratumumab based therapy without upfront plerixafor administration among patients affected by NDMM., Materials and Methods: Clinical, mobilization and clonogenic data from 41 consecutively enrolled NDMM patients were analyzed. Patients underwent collection of autologous CD34+ by apheresis at the ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy, from January 2021 to March 2023. Clonogenicity analysis was performed on BFU-E and CFU-GM., Results: Seventy-five percent of daratumumab-treated patients underwent >1 apheresis, compared to 24% of non-daratumumab patients (p=0.0017). Daratumumab-treated patients had significantly lower CD34+ count (mean 38 vs 79/μL, respectively; p=0.0011), with a median CD34+ harvest of 3.98×10 6 /kg (range 1.68-9.18) vs 6.87×10 6 /kg (range 1.63-16.85) in non-daratumumab-treated (p=0.0006). In multivariate analysis the likelihood of undergoing >1 apheresis was significantly higher in older patients (OR 1.2, 95% CI 1-1.4, Z=2.10, p=0.03) and daratumumab-treated patients (OR 15, 95% CI 2.8-129, p=0.004). Moreover, daratumumab-based induction therapy demonstrated an independent negative association with BFU-E colony formation (p=0.0148), even when accounting for patient age and CD34+ levels., Discussion: Our findings underscore the impact of daratumumab-based treatment on CD34+ mobilization in a real-life, upfront plerixafor-free population of NDMM patients. Higher probability of requiring multiple apheresis occurred among daratumumab-treated patients. Interestingly, the observation that daratumumab might negatively impact BFU-E colony formation, independent of CD34+ cell count, offers novel biological perspectives. Appropriate strategies should be adopted by the Apheresis teams to mitigate these potential negative effects. more...