Lack of durable disease control with chemotherapy for mycosis fungoides and Sézary syndrome: a comparative study of systemic therapy.

Numerous systemic treatment options exist for patients with mycosis fungoides (MF) and Sézary syndrome (SS), but no large comparative studies are published. To study the efficacy of treatments, a retrospective analysis of our cutaneous lymphoma database was undertaken, with 198 MF/SS patients undergoing systemic therapies. The primary end point was time to next treatment (TTNT). Patients with advanced-stage disease made up 53%. The median follow-up time from diagnosis for all alive patients was 4.9 years (range 0.3-39.6), with a median survival of 11.4 years. Patients received a median of 3 lines of therapy (range 1-13), resulting in 709 treatment episodes. Twenty-eight treatment modalities were analyzed. The median TTNT for single- or multiagent chemotherapy was only 3.9 months (95% confidence interval [CI] 3.2-5.1), with few durable remissions. α-interferon gave a median TTNT of 8.7 months (95% CI 6.0-18.0), and histone deacetylase inhibitors (HDACi) gave a median TTNT of 4.5 months (95% CI 4.0-6.1). When compared directly with chemotherapy, interferon and HDACi both had greater TTNT (P < .00001 and P = .01, respectively). This study confirms that all chemotherapy regimens assessed have very modest efficacy; we recommend their use be restricted until other options are exhausted.

Autologous hematopoietic stem cell transplantation for multiple myeloma in the age of CAR T cell therapy.

Chimeric antigen receptor (CAR) T cell therapy has revolutionized the management of relapsed and refractory myeloma, with excellent outcomes and a tolerable safety profile. High dose chemotherapy with autologous hematopoietic stem cell transplantation (AHCT) is established as a mainstream of newly diagnosed multiple myeloma (NDMM) management in patients who are young and fit enough to tolerate such intensity. This standard was developed based on randomized trials comparing AHCT to chemotherapy in the era prior to novel agents. More recently, larger studies have primarily shown a progression free survival (PFS) benefit of upfront AHCT, rather than overall survival (OS) benefit. There is debate about the significance of this lack of OS, acknowledging the potential confounders of the chronic nature of the disease, study design and competing harms and benefits of exposure to AHCT. Indeed upfront AHCT may not be as uniquely beneficial as we once thought, and is not without risk. New quadruple-agent regimens are highly active and effective in achieving a deep response as quantified by measurable residual disease (MRD). The high dose chemotherapy administered with AHCT imposes a burden of short and long-term adverse effects, which may alter the disease course and patient's ability to tolerate future therapies. Some high-risk subgroups may have a more valuable benefit from AHCT, though still ultimately suffer poor outcomes. When compared to the outcomes of CAR T cell therapy, the question of whether AHCT can or indeed should be deferred has become an important topic in the field. Deferring AHCT may be a personalized decision in patients who achieve MRD negativity, which is now well established as a key prognostic factor for PFS and OS. Reserving or re-administering AHCT at relapse is feasible in many cases and holds the promise of resetting the T cell compartment and opening up options for immune reengagement. It is likely that personalized MRD-guided decision making will shape how we sequence in the future, though more studies are required to delineate when this is safe and appropriate.

Design, implementation and clinical utility of next generation sequencing in myeloid malignancies: acute myeloid leukaemia and myelodysplastic syndrome.

Next generation sequencing (NGS) based technology has contributed enormously to our understanding of the biology of myeloid malignancies including acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS). Assessment of clinically important mutations by NGS is a powerful tool to define diagnosis, determine prognostic risk, monitor measurable residual disease and uncover predictive mutational markers/therapeutic targets, and is now a routine component in the workup and monitoring of haematological disorders. There are many technical challenges in the design, implementation, analysis and reporting of NGS based results, and expert interpretation is essential. It is vital to distinguish relevant somatic disease associated mutations from those that are known polymorphisms, rare germline variants and clonal haematopoiesis of indeterminate potential (CHIP) associated variants. This review highlights and addresses the technical and biological challenges that should be considered before the implementation of NGS based testing in diagnostic laboratories and seeks to outline the essential and expanding role NGS plays in myeloid malignancies. Broad aspects of NGS panel design and reporting including inherent technological, biological and economic considerations are covered, following which the utility of NGS based testing in AML and MDS are discussed. In current practice, patient care is now strongly shaped by the results of NGS assessment and is considered a vital piece of the puzzle for clinicians as they manage these complex haematological disorders.

Optimal oral cyclosporin dosing with concomitant posaconazole post allogeneic stem cell transplantation.

Cyclosporin is an immunosuppressive agent in allogeneic hematopoietic stem cell transplantation and its metabolism is strongly affected by concomitant drugs, including posaconazole which is now extensively used as anti-fungal prophylaxis post-allograft. We undertook a retrospective audit of 29 patients undergoing their first allograft who were receiving posaconazole at the time of transition from intravenous to oral cyclosporin. This group had a median initial oral cyclosporin dose of 2.58 mg/kg bd (range 1.75-3.95) and high incidence of cyclosporin-related toxicity was noted, requiring significant dose reductions such that by day 60 the media dose was 1.60 mg/kg bd (range 0.86-3.33). We subsequently amended our dosing protocol and analyzed a further 20 patients specifying an initial oral cyclosporin dose of 2.25 mg/kg bd and found this had little impact on toxicity or requirement for dose reductions. Starting doses of no greater than 2 mg/kg bd appear optimal to prevent toxicity in allograft recipients receiving concomitant posaconazole.