Paroxysmal nocturnal hemoglobinuria (PNH)

Persistent hemolytic anemia and a lack of oral treatments are challenges for patients with PHN who have received anti-C5 therapy or have not received complement inhibitors. Results were published of two phase 3 open-label clinical trials with iptacopan (a first-in-class oral proximal complement inhibitor that targets factor B): APPLY-PNH (NCT04558918), a randomized trial involving patients with PNH who had persistent anemia despite anti-C5 treatment (eculizumab or ravulizumab at least 6 months before randomization), and APPOINT-PNH (NCT04820530), a single-group trial involving patients with hemolytic PNH who had not previously received complement inhibitor therapy. 

In the first trial, anti–C5–treated patients were randomly assigned to switch to iptacopan or to continue anti-C5 therapy. The primary endpoints were an increase in hemoglobin level without red-cell transfusion. Of 60 patients who received iptacopan, 51 had an increase in hemoglobin level of at least 2 g per deciliter from baseline (difference, 80 percentage points [95% CI, 71–88]), and 42 patients had a hemoglobin level of at least 12 g per deciliter (difference, 67 percentage points [95% CI, 56–77], P<0.001), each without transfusion; none of the 35 anti-C5–treated patients attained the endpoint levels. In the second trial, 31 of 33 patients had an increase in hemoglobin level of at least 2 g per deciliter from baseline without red-cell transfusion (estimated percentage of patients: 92 [95% CI, 82–100]). Additionally, iptacopan reduced fatigue, reduced levels of reticulocyte and bilirubin, and resulted in mean lactate dehydrogenase (LDH) levels that were less than 1.5 times the upper limit of the normal range. Headache was the most frequent (up to 11%) adverse event with iptacopan. This data shows that blocking the complement system proximally at the alternative pathway with monotherapy with an oral factor B inhibitor was effective and safe and did not lead to the use of additional combined terminal blockade. 

Acute myeloid leukemia (AML)

Allogeneic hematopoietic cell transplantation (HCT) improves outcomes for patients with AML harboring an FLT3-ITD mutation. These patients are routinely treated with an FLT3 inhibitor after HCT, but there is limited evidence to support this. The MORPHO study (NCT02997202) was a phase 3 double-blinded, placebo-controlled trial, in patients with FLT3-ITD AML (n=356) in first remission who underwent HCT and were randomly assigned to placebo or 120 mg gilteritinib once daily for 24 months after HCT. Although relapse free survival (RFS, primary endpoint) was higher in the gilteritinib arm, the difference was not statistically significant (hazard ratio [HR], 0.679 [95% CI, 0.459 to 1.005]; two-sided P =0.0518). However, 50.5% of patients had measurable residual disease (MRD) detectable pre- or post-HCT, and, in a pre-specified subgroup analysis, gilteritinib was beneficial in this population (HR, 0.515 [95% CI, 0.316 to 0.838]; P = .0065). Those without detectable MRD showed no benefit (HR, 1.213 [95% CI, 0.616 to 2.387]; P = 0.575).

Chronic myeloid leukemia (CML)

Achieving treatment-free remission (TFR) has now become a new goal in CML management. However, the prognostic indicators for sustained TFR are still not well established. The European Stop Kinase Inhibitors (EURO-SKI) study (NCT01596114) is the largest prospective non-randomized study for investigating the cessation of tyrosine kinase inhibitors (TKIs) in patients with CML in stable deep molecular response (DMR). The authors presented the final analysis of the EURO-SKI trial after 3 years of follow-up and the prognostic factors for short- and long-term molecular response maintenance. Among 728 patients, 434 patients (61%; 95% CI, 57 to 64) remained in major molecular response (MMR) at 6 months, and 309 patients of 678 (46%; 95% CI, 42 to 49) at 36 months. Duration of TKI treatment and DMR before TKI stop were confirmed as significant factors for the prediction of MMR loss at 6 months. In addition, the type of BCR::ABL1 transcript was identified as a prognostic factor. For late MMR losses after 6 months, TKI treatment duration, percentage of blasts in peripheral blood, and platelet count at diagnosis were significant factors in a multivariate analysis. For the entire study period of 36 months, multiple logistic regression models confirmed the duration of treatment, blasts, and transcript type as independent factors for MMR maintenance. In addition to the duration of treatment, transcript type as well as blasts in peripheral blood at diagnosis should be considered important factors to predict treatment-free remission.

Autoimmune hemolytic anemia (AIHA)

One-third of patients with AIHA show inadequate bone marrow (BM) compensatory response with inappropriately low levels of reticulocytes and endogenous erythropoietin. Ineffective BM compensation is associated with more severe anemia, transfusion need, and hospital admission, and treatment with recombinant erythropoietin (rEPO) may be beneficial. A recent study (NCT05931718) examined the efficacy and safety of rEPO in a single-center cohort of 47 patients with AIHA with inadequate reticulocytosis and endogenous erythropoietin at baseline. Epoetin alpha 40 000 international units/week were administered subcutaneously until hemoglobin (Hb) >11 g/dL and then tapered off. Overall response was 55% at 15 days, 74% at 1 month, 74% at 3 months, 80% at 6 months, and 91% at 12 months. Consistently, Hb values significantly increased from baseline to each subsequent time point (P<.001). Transfusion needs were reduced from 30% to <10% at 15 days and thereafter (P<.001). No association between concomitant medications and response to rEPO was found. The comparison with an AIHA population not treated with rEPO showed a significant benefit of rEPO at 15 days and 1 month on response and Hb increase. Treatment was effective independent of AIHA subtype, and safe without increased risk of thrombosis.

IACH Friends and Members Corner

FDA APPROVES FIRST EVER BTK INHIBITOR TO TREAT LYMPHOMA SUBTYPE

Rye Brook, N.Y., March 14, 2023 – The U.S. Food and Drug Administration approved zanubrutinib (Brukinsa®) in combination with obinutuzumab (Gazyva®) to treat adults whose follicular lymphoma has returned or progressed despite earlier treatment. 

The accelerated approval, which the FDA announced last week, was based on a higher and longer duration of response in patients treated with the combination of zanubrutinib and obinutuzumab compared to obinutuzumab alone.

Click here to read the full article

This corner is yours! Please send us any information you would like to share with the IACH community (Upcoming event, congratulations message, award announcement, call for a grant, new important appointment, vacant position, etc) to info@clinical-hematology.org.