Primary immune thrombocytopenia (ITP) therapies

Mazzucconi et al,  recently published results of a phase 3 clinical trial (NCT00657410) that compared  standard-dose prednisone (PDN, 1mg/kg/day from days 0 to 28) [arm A, n=59]  and high-dose dexamethasone (HD-DXM, 40 mg/day for 4 days, every 14 days, for 3 consecutive courses) [arm B, n=54]  as first-line treatment for adult patients with newly diagnosed untreated primary ITP.  These results confirm that corticosteroids are a safe and effective first-line treatment for adults with newly diagnosed ITP.  After a median follow-up of 44.4 months, total initial responses (complete response [CR], partial response [PR], minimal response [MR]) were 44 of 56 (78.57%) in Arm A and 46 of 49 (93.88%) in Arm B at days 42 and 46, respectively (p=0.0284). Total final responses (at day 180 from the initial response) were 26 of 43 (60.47%) in Arm A and 23 of 39 (58.97%) in Arm B (p=0.8907). Total persistent responses (at 12 months from the initial response) were 25 of 31 (80.65%) in Arm A and 20 of 36 (55.56%) in Arm B (p=0.0292). Seven relapses occurred. Overall disease-free survival was 81.11% at 48 months from day 180. PDN and pulsed HD-DXM were well tolerated; only 9 patients experienced ≥1 adverse drug reactions,  mostly in Arm A (7 patients). HD-DXM exhibits a better initial response, whereas PDN seems to increase long-lasting responses. For future studies, a combination of HD-DXM with other effective agents such as thrombopoietic agents seems worthy of further investigation. 

Primary testicular lymphoma (pTL)

Primary testicular diffuse large B-cell lymphoma is characterized by high risk of contralateral testis and central nervous system (CNS) relapse. The IELSG30 phase 2 study investigated feasibility and activity of an intensified intrathecal (IT) and intravenous (IV) CNS prophylaxis. All patients had diagnostic orchiectomy. Patients with stage I/II pTL who had not received treatment received 2 cycles of IV high-dose methotrexate (MTX, 1.5 g/m2) after 6 cycles of the R-CHOP regimen. IT liposomal cytarabine was administered on day 0 of cycles 2 to 5 of a 21-day R-CHOP regimen. Contralateral testis radiotherapy (25-30 Gy) was recommended. 54 patients (median age: 66 years) were treated with R-CHOP, 53 received at least 3 doses of IT cytarabine, 48 received at least 1 dose of IV MTX, and 50 received prophylactic radiotherapy. No unexpected toxicity occurred. At a median follow-up of 6 years, there was no CNS relapse; 7 patients progressed, and 8 died, with 5-year progression-free and overall survival rates of 91% (95% confidence interval [CI], 79-96) and 92% (95% CI, 81-97), respectively. Extranodal recurrence was documented in 6 patients (2 without nodal involvement). In 4 cases, the relapse occurred >6 years after treatment. Causes of death were lymphoma (n = 4), second primary malignancy (n = 1), cerebral vasculopathy (n = 1), unknown (n = 2). Authors conclude that intensive prophylaxis was feasible and effective in preventing CNS relapse.

Hemophilia B

Etranacogene dezaparvovec (an adeno-associated viral vector expressing the hyperfunctional factor IX Padua variant targeting the liver), the first gene therapy approved (by the US Food and Drug Administration, the European Medicines Agency, in Canada and the UK) for hemophilia B treatment, was shown to be superior to treatment with continuous prophylactic factor IX in terms of bleeding protection 18 months after gene therapy in a phase 3 trial (HOPE-B). Recently, the authors reported post-hoc 24-month efficacy and safety data from this trial. For patients, the data provide reassurance that etranacogene dezaparvovec  can provide meaningful and stable correction of hemophilia B for at least 2 years.  The phase 3 HOPE-B trial (NCT03569891) enrolled males aged ≥18 years with inherited haemophilia B, classified as severe (plasma factor IX activity level <1%) or moderately severe (plasma factor IX activity level ≥1% and ≤2%), with a severe bleeding phenotype and who were on stable continuous factor IX prophylaxis. 54 participants were treated with a single infusion of etranacogene dezaparvovec. The primary endpoint (reported previously), was non-inferiority of the annualised bleeding rate (ABR) during the 52 weeks following stable factor IX expression (defined as months 7–18 after treatment) versus at least a 6-month lead-in period in which participants received their usual continuous factor IX prophylaxis; and is updated here up to month 24.  In the updated analysis comparing months 7–24 after gene therapy to the lead-in period, mean adjusted ABR significantly reduced from 4.18 to 1.51 (p=0·0002) for all bleeds and from 3.65 to 0.99 (p=0·0001) for factor IX-treated bleeds. During each 6-month period after gene therapy, at least 67% of participants experienced no bleeding (36 of 54 during months 0–6 and stable thereafter), compared with 14 (26%) of 54 during the lead-in period. 96% of participants expressed endogenous factor IX, remaining free of factor IX prophylaxis at month 24. No new safety issues were found, and there were no significant side effects or treatment-related deaths.

Paroxysmal nocturnal hemoglobinuria (PNH

Recently, Blood published the experience of patients with PNH-related thrombosis in a large real-world cohort of PNH patients from four US centers. The study explored thrombotic events (TE) and anti-coagulation strategies. Regarding the therapy of thromboembolic consequences in this context, there are no established recommendations; instead, individual practices determine the type and duration of anticoagulation.  Among 267 patients followed-up for a total of 2043 patient/years, 56 (21%) developed TE. This occurred at disease onset in 43% of cases, involving more often the venous system, typically as Budd-Chiari syndrome. Patients receiving complement inhibitors had a reduced rate of TE (21 versus 40 TE per 1000 patient/years in untreated cases, with a 2-year cumulative incidence of thrombosis of 3.9% versus 18.3% respectively), and varied according to PNH granulocytes and erythrocytes clone size, type, disease activity parameters, as well as number (≥2 mutations or less) and variant allelic frequency of PIGA mutations. Anti-coagulation with warfarin (39%), direct oral anti-coagulants [DOACs] (37%), and low-molecular-weight heparin (16%) was administered for a median of 29 months (9-61.8). No thrombotic recurrence was observed in 19 patients treated with DOACs at a median observation of 17.1 months (8.9-45) while 14 cases discontinued anti-coagulation without TE recurrence at a median time of 51.4 months (29.9-86.8). DOACs are potential options for PNH-related thrombosis and discontinuation is safe in cases with complete control of intravascular hemolysis.

Multiple myeloma (MM)

Hoff et al, analyzed the real-world prevalence and efficacy of once-weekly (1-w) versus twice-weekly (2-w) bortezomib regimens in newly diagnosed MM. 1-w bortezomib is clearly associated with similar efficacy and fewer toxicities compared to 2-w bortezomib. They analyzed 2497 US patients aged 18–70 years treated with commercial first-line bortezomib, including 910 (36.4%) patients who received 2-w and 1522 (63.2%) who received 1-w bortezomib. 1-w bortezomib use increased over time, from 57.7% in 2017 to 73.1% in 2022. Multivariate analysis identified worsened performance status and more recent year of diagnosis with higher odds of receiving 1-w bortezomib. Progression-free survival (median 37.2 months with 1-w versus 39.6 months with 2-w, p=0.906) and overall survival (medians not reached in either cohort, p=0.800) were comparable. Polyneuropathy rates were higher in patients receiving 2-w bortezomib (34.7% versus 18.5%, p< 0.001).

Hematopoietic cell transplantation (HCT) and cellular therapies.

The EBMT reported that CAR-T therapy activity continues to grow; transplant activity has slowed in Europe. In 2022, 46143 HCT (comprising 19011 [41.2%] allogeneic and 27132 [58.8%] autologous). 4329 patients received advanced cellular therapies, 3205 (74%) of which were CAR-T. Changes compared to the previous year were an increase in CAR-T treatments (+27%) and decrease in allogeneic (−4.0%) and autologous HCT (−1.7%). Main indications for allogeneic HCT were myeloid malignancies (58.4%), lymphoid malignancies (26.2%) and non-malignant disorders (14.4%). Main indications for autologous HCT were  plasma cell disorders (57.1%), lymphomas (32.9%), and solid tumors (6.6%). In allogeneic HCT, use of sibling donors decreased by −7.7%, haploidentical donors by −6.3% and unrelated donors by −0.9%. Overall cord blood HCT decreased by −16.0%. Use of allogeneic, and to a lesser degree autologous HCT, decreased for lymphoid malignancies likely reflecting availability of new treatment strategies.  The rate at which adults are using HCT appears to have slowed down after years of steady increase.