Combined application of targeted therapy and immunotherapy in chronic myeloid leukaemia

Combining vaccination against leukaemia-derived antigens and treatment with tyrosine kinase inhibitors (TKI) in chronic phase CML is potentially a promising strategy to eradicate a reservoir of TKI resistant leukaemic cells. Previous studies have documented conflicting effects of TKIs on the immune response. I aimed to determine the in vivo immunomodulatory effects of TKIs on T and B-cell immune responses to antigens in patients with CML on TKIs. I first demonstrated that that the B-cell response to H1N1 influenza vaccine was significantly better in patients with CML compared to patients with other haematological malignancies. I then performed a more comprehensive analysis of T and B cell responses to a viral (seasonal influenza) and bacterial (pneumococcus) vaccine. I did not find a significant quantitative or qualitative difference in T cell responses to influenza vaccine in patients with CML on TKI compared to controls. However, I demonstrated that CML patients on TKIs have impaired IgM responses to pneumococcal vaccine, associated with lower frequencies of IgM memory B cells. Moreover, treatment with imatinib was associated with a significant reduction in IgM memory B cells. In vitro co-incubation of B-cells with plasma from CML patients on TKI or directly with imatinib, dasatinib or nilotinib, induced a dose-dependent inhibition of Bruton's tyrosine kinase, a tyrosine kinase essential for B cell signalling and survival. These data suggest that the loss of memory B-cell subsets and impaired humoral immune responses may be driven by the off-target kinase inhibitory activity of TKIs. I further explored the implications of Philadelphia positive (Ph+) lymphopoiesis on B cell function. I found that nearly 50% of CML patients at diagnosis have evidence of Ph+ B lymphopoiesis. Interestingly, the presence of Ph+ B cells predicted for worse prognosis, suggesting the involvement for a more committed progenitor with biphenotypic self-renewal capacity

Autoimmune hemolytic anemia after allogeneic hematopoietic stem cell transplantation: analysis of 533 adult patients who underwent transplantation at King's College Hospital.

Autoimmune hemolytic anemia (AIHA) is a recognized complication of hematopoietic stem cell transplantation (HSCT); it is often refractory to treatment and carries a high mortality. To improve understanding of the incidence, risk factors, and clinical outcome of post-transplantation AIHA, we analyzed 533 patients who received allogeneic HSCT, and we identified 19 cases of AIHA after HSCT (overall incidence, 3.6%). The median time to onset, from HSCT to AIHA, was 202 days. AIHA was associated with HSCT from unrelated donors (hazard ratio [HR], 5.28; 95% confidence interval [CI], 1.22 to 22.9; P = .026). In the majority (14 of 19; 74%) of AIHA patients, multiple agents for treatment were required, with only 9 of 19 (47%) patients achieving complete resolution of AIHA. Patients with post-transplantation AIHA had a higher overall mortality (HR, 2.48; 95% CI, 1.33 to 4.63; P = .004), with 36% (4 of 11 cases) of deaths attributable to AIHA

De-escalation of tyrosine kinase inhibitor dose in patients with chronic myeloid leukaemia with stable major molecular response (DESTINY): an interim analysis of a non-randomised, phase 2 trial

BACKGROUND: Discontinuation of tyrosine kinase inhibitor (TKI) therapy is feasible for some patients with chronic myeloid leukaemia (CML) with deep molecular responses, defined as stable MR4 (BCR-ABL1/ABL1 ratio 0.1%) on two consecutive samples. The study endpoint is the proportion of patients who lose their MMR on de-escalation and regain MMR on TKI resumption. The trial was registered at https://clinicaltrials.gov/ as NCT 01804985.FINDINGS: During the 12 months of half-dose therapy, 12 patients had molecular recurrence, all of whom regained MMR within 4 months of full dose TKI resumption. Recurrence was lower in the MR4 cohort (3 of 121 evaluable patients; 2.5%, 90% CI: 0.2-4.8%) than in the MMR cohort (9 of 48 evaluable patients; 18.8%, 90% CI: 9.5-28%) (p = 0.0007), but was unrelated to prior TKI or TKI therapy duration. Many adverse events improved during the first 3 months of de-escalation, though not thereafter. Overall, de-escalation saved 46.7% from an expected TKI budget (without de-escalation) of £4,156,969.INTERPRETATION: TKI de-escalation is safe for the vast majority of patients with excellent responses to TKI therapy, and is associated with improvement in symptoms and significant financial savings. The data imply that lower TKI doses may maintain responses in these patients

Greffe allogénique avec conditionnement à intensité réduite dans les lymphomes malins non hodgkiniens

AIX-MARSEILLE2-BU Méd/Odontol. (130552103) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Greffe allogénique avec conditionnement à intensité réduite dans les lymphomes malins non hodgkiniens

AIX-MARSEILLE2-BU Méd/Odontol. (130552103) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Patients in Focus: What's Relevant for Chronic Myeloid Leukaemia and Philadelphia Chromosome-Positive Acute Lymphoblastic Leukaemia?

This symposium was dedicated to discussing BCR-ABL-positive chronic myeloid leukaemia (CML) and Philadelphia-positive acute lymphoblastic leukaemia (Ph+ALL). Prof Baccarani opened the symposium, highlighting the recent improvements in survival in patients with BCR-ABL-positive CML and Ph+ALL. Dr de Lavallade discussed the role of mutational analyses as part of molecular monitoring, including the use of next-generation sequencing (NGS) to assess BCR-ABL mutation status and to detect low-frequency mutations. Dr Rea reviewed treatment options for CML with tyrosine kinase inhibitors (TKI) in the second and third-line treatment settings. The session concluded with Dr Martinelli presenting mutational burden in Ph+ALL patients and treatment options for these patients, in particular, with ponatinib, emphasising the importance of early treatment initiation