STEROIDS VS ELTROMBOPAG FOR FIRST AND SECOND-LINE TREATMENT OF ADULT IMMUNE THROMBOCYTOPENIA

Primary immune thrombocytopenia (PIT) is characterized by the progressive destruction of platelets through the formation of antibodies on the different glycoproteins of the plate let membrane. Both the approach and the handling have changed significantly in the past decade, putting more value into the asymptomatic thrombocytopenia, as well as the risk of death from severe thrombocytopenia, going from the steroids and the splenectomy, and up to the inclusion of monoclonal antibodies, analogs of the TPO receptor, and the inhibitors of splenic tyrosine kinase to the different lines of treatment. At present, steroids persevere as first-line treatment. Both prednisone and dexamethasone are the most used steroids, with a response between 60-80%, while the usage of methylprednisolone has been substituted due to a lack of controlled trials. The second-line treatment has also evolved since the inclusion of anti-CD20 therapies and TPO analogs (Eltrombopag), acting as a bridging strategy towards a splenectomy or as maintenance. Eltrombopag is an oral thrombopoietin receptor agonist that stimulates TPO signaling, stimulating the production of functional platelets. It is considered a tolerable drug, but it warrants monitoring of liver function and cell counts due to the risk of fibrosis. In Mexico, steroids are used as first-line treatment, and Eltrombopag has been incorporated into therapeutic approaches in recent times.
The aim of the study- carried out by Carlos Martínez Murillo et al.- is to evaluate the response of steroids as a first-line treatment and Eltrombopag as a second-line regimen.
A retrospective, observational study was conducted based on the clinical records of patients diagnosed with primary immune thrombocytopenia between 2018 and 2023 at Hospital General de México, “Dr. Eduardo Liceaga,” in Mexico City.
Two hundred forty-two patients were studied; 192 were considered for first-line treatment, and 50 received Eltrombopag as second-line therapy. The average platelet count before starting the treatment was 9.6 x 103/µl, with most cases (72.3%) presenting counts below 10 x 103/µl. No significant differences were observed in terms of severity between both types of treatment. Nevertheless, the proportion of cases with severe thrombocytopenia was slightly higher in the group treated with Eltrombopag (80% versus 70.3%), while, in terms of higher counts, a higher number of patients in the first-line group were found (27.6% vs 20% for counts between 11–50 x 103/µl and 100% vs 0 in counts above 51 x 103/µl.
A higher proportion of hemorrhagic events was observed in patients treated with steroids in comparison with those who received Eltrombopag (65.2% vs 34.8%, p=0.000, CI of 95%). 69.8% of patients treated with steroids achieved complete remission, compared to 80% of those in the Eltrombopag group. 64% (n=32) of Eltrombopag patients achieved complete response, 24% (n=12) had partial response, and 12% (n=6) had stable disease. No significant differences were found in the dependent variables for the resolution of relapse. Furthermore, age above 40 years was a risk factor (OR: 1.77, 1.01 – 3.13 CI95%; p< 0.05) for platelet count failure.
Corticosteroids remain an efficient first-line treatment, especially when using prednisone or Dexamethasone; in terms of second-line treatment, Eltrombopag is a safe treatment with a higher proportion of responses in patients without a history of splenectomy and without the joint use of the steroid, which suggests that it might also be an option for first-line treatment.

MANAGING CHEMOTHERAPY-INDUCED THROMBOCYTOPENIA (CIT) WITH ELTROMBOPAG; A RETROSPECTIVE REAL-WORLD ANALYSIS

CIT (Chemotherapy-induced thrombocytopenia) is a known and debilitating complication of anticancer treatments. CIT may cause delays and disruptions in anticancer treatment; examples include partial treatment stoppage, treatment application outside of the recommended dose and duration, and dosage adjustments. CIT poses a significant clinical challenge in cancer treatment, leading to an increased risk of bleeding and dose reductions or delays in chemotherapy. Eltrombopag, a thrombopoietin receptor agonist, has shown promise in managing CIT. However, data on its efficacy and safety in this specific population remain limited.
This retrospective multicenter study, led by Mehmet Baysal et al., aimed to evaluate the efficacy and safety of eltrombopag in managing chemotherapy-induced thrombocytopenia in cancer patients. Specifically, the authors sought to assess changes in platelet counts, incidence of bleeding events, and adverse effects associated with eltrombopag therapy.
The authors conducted a retrospective analysis of 21 cancer patients with chemotherapy-induced thrombocytopenia who received eltrombopag treatment across four medical centers between 2021-and January 2024. Patient demographics, cancer types, chemotherapy regimens, baseline platelet counts, eltrombopag dosages, and treatment durations were collected from medical records. The primary outcomes included changes in platelet counts following eltrombopag initiation, success in continuing chemotherapy incidence of bleeding events during treatment, and adverse effects related to eltrombopag therapy. Eltrombopag started at 50 mg/day before the planned chemotherapy regimen. Statistical analyses were performed to assess the significance of observed changes and associations.
A total of 21 patients were included in our analysis. Fourteen were female and 7 were male. The median age of the patients was 63 ranging between 41 and 85. Breast cancer as the most prevalent solid tumor type (n=7), followed by lung (n=3) and gynecologic (n=3) malignancies. Other tumor types included stomach (n=2), pancreas (n=2), prostate (n=2), mesothelioma (n=1), and CNS (central nervous system) (n=1). Fourteen patients (66.7 %) had stage IV disease, 6 patients (28.6 %) had stage III disease and one patient (4.7 %) had stage one disease. Patients had a median of 2 prior chemotherapy regimens, ranging from 1 to 5. The median delay in chemotherapy treatment was 5 weeks (3-18). Median Thrombocyte count before starting Eltrombopag treatment was 34 x 109/L. The median duration of eltrombopag usage was 8 weeks. Patients got a median 2.5 cycles of chemotherapy after eltrombopag. After beginning eltrombopag treatment, the median platelet count values were found to be 73, 86, 132, and 108 x 109/L in the first week, 4th week, 6th week, and 12th week respectively. While grade 1 liver transaminase elevation was detected in 3 patients, no other side effects were observed.
These findings suggest that pre-chemotherapy administration of eltrombopag may be a promising strategy for managing chemotherapy-induced thrombocytopenia in cancer patients. These findings highlight the possible benefits of eltrombopag as a kind of supportive care for cancer patients receiving chemotherapy. Larger sample sizes and additional prospective studies are needed to confirm these results and clarify the best ways to dose and time eltrombopag in this particular population.

EFFECTS OF ORAL IPTACOPAN MONOTHERAPY, INCLUDING INCREASED PAROXYSMAL NOCTURNAL HEMOGLOBINURIA RED BLOOD CELL CLONE SIZE, ARE MAINTAINED IN COMPLEMENT INHIBITOR-NAÏVE PATIENTS: FINAL APPOINT-PNH DATA

Iptacopan (a first-in-class, oral factor B inhibitor) demonstrated efficacy and safety as a monotherapy in the 24- week (wk) core treatment period of the Phase III APPOINT-PNH trial (NCT04820530) in complement inhibitor naive patients (pts) with hemolytic paroxysmal nocturnal hemoglobinuria (PNH).
The authors (Antonio Maria Risitano et al.) report final (48-wk) efficacy and safety data from APPOINT-PNH, including PNH red blood cell (RBC) clone size and C3 fragment deposition data.
Complement inhibitor-naïve adult PNH pts with hemoglobin (Hb) 1.5 × upper limit of normal received iptacopan monotherapy 200 mg twice daily for 48 wks (24-wk core period and 24-wk extension period).
All 40 pts completed APPOINT-PNH. The proportion of pts with non-missing data achieving an Hb increase of ≥2 g/dL from baseline (irrespective of transfusions) was maintained from Wk 24 (37/39, 94.9%) to Wk 48 (38/39, 97.4%). The proportion of pts achieving Hb ≥12 g/dL (irrespective of transfusions) at Wk 48 (31/39, 79.5%) was numerically higher than at Wk 24 (26/39, 66.7%). An estimated 97.5% of pts (95% confidence interval [CI] 92.5, 100.0) achieved transfusion avoidance, with one pt requiring RBC transfusions between Wks 2 and 48. Mean Hb was 12.56 g/dL (standard deviation [SD] 1.49) at Wk 24 and increased to 13.24 g/dL (SD 1.80) at Wk 48 (mean change from baseline to Wk 48 +5.09 g/dL [SD 2.01]), showing further improvement.
Increased Functional Assessment of Chronic Illness Therapy – Fatigue scores at Wk 24 were sustained through the extension period (mean change from baseline to Wk 48 +10.4 [SD 10.14]), as were reductions in LDH (median change from baseline to Wk 48 −1241.5 U/L [interquartile range −1795.0 to −925.0]; Wk 48 median 261.5 U/L [interquartile range 206.0 to 334.0] ) and absolute reticulocyte count (mean change from baseline to Wk 48 −76.55 × 109 /L [SD 50.15]). The total PNH RBC clone size (type II and III) at Wk 24 (mean 87.06% [SD 9.89%]) was sustained through to Wk 48 (mean 87.77% [SD 11.44%]; mean change from baseline to Wk 48 +43.62% [SD 19.01%]; Figure); mean C3 fragment deposition on PNH RBCs remained negligible (0.11% at Wk 24 and 0.36% at Wk 48).
Two pts experienced a clinical breakthrough hemolysis (BTH) event during the extension period (adjusted annualized rate: 0.05 [95% CI 0.01, 0.17]), which resolved without treatment discontinuation (one resolved during APPOINT-PNH, one after the 48-wk period). Potential complement-amplifying conditions (CACs) were identified for both pts. There were no major adverse vascular events.
The most common treatment-emergent adverse events in the trial were headache (30.0% of pts), COVID-19 (22.5%), upper respiratory tract infection (17.5%) and diarrhea (15.0%). There were no deaths or treatment discontinuations.
Improvements in the 24-wk core treatment period of APPOINT-PNH were sustained over the extension period, including maintenance of increased Hb, normal/near-normal mean Hb, improvements in fatigue and transfusion avoidance. The increase in total PNH RBC clone size after 24 wks of therapy was sustained through the extension period, indicating continued control of hemolysis and hence survival of PNH RBCs. Despite the increased PNH RBC clone size, clinical BTH was only observed in two pts, both of whom had potential CACs. C3 fragment deposition was negligible during 48 wks of treatment, supporting no emergence of C3-mediated extravascular hemolysis. Iptacopan was also well tolerated throughout APPOINT-PNH. These findings suggest that iptacopan monotherapy could be a practice-changing treatment for hemolytic PNH.

PATIENT EXPERIENCE OF IPTACOPAN IN THREE CLINICAL TRIALS FOR PAROXYSMAL NOCTURNAL HEMOGLOBINURIA

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired, clonal hematological disorder characterized by intravascular hemolysis, thrombosis, and bone marrow failure. Along with smooth muscle dystonia and hemoglobinuria, symptoms of PNH also include chronic and severe fatigue which significantly impacts patients’ health-related quality of life. Data suggests a substantial proportion of patients on intravenous antiC5 antibody therapies do not achieve normal or near normal hemoglobin levels.
Iptacopan is a novel orally administered proximal complement inhibitor treatment for PNH, that has demonstrated efficacy and safety in two Phase 3 clinical trials, APPLY-PNH (NCT0482053019) and APPOINT-PNH (NCT0455891820), and is being further explored in a roll-over extension (NCT04747613).
Qualitative in-trial interviews were conducted by the authors (Carlos de Castro et al.) with a subset of patients involving diverse populations with varying cultural backgrounds and languages in the three clinical trials to better understand changes in PNH symptoms they experienced since beginning treatment with iptacopan, and their perceptions of and preference for iptacopan.
Clinical sites in eight countries, the United States, United Kingdom, China, France, Germany, Italy, Japan, and Spain, obtained informed consent from a total of 61 PNH patients enrolled in the three clinical trials to take part in the qualitative in-trial interviews. Interviewers trained in qualitative research techniques conducted audio-recorded telephone interviews with patients in their local language using a semi-structured interview guide designed to capture spontaneous and probed reports from patients about their treatment experience. Audio recordings were transcribed verbatim, translated into English (if applicable), and anonymized. Transcripts were coded and analyzed using qualitative data analytic methods.
In describing changes to their PNH symptoms, ≥90.0% of interviewed patients across the three trials who experienced PNH symptoms prior to their treatment with iptacopan reported that their symptoms improved with treatment (see Table 1). In describing their perceptions of iptacopan, all 22 patients in the roll-over extension trial who completed interviews indicated that they were either very satisfied (n=14, 63.6%) or satisfied (n=8, 36.4%) with iptacopan; and all 18 patients who were asked reported that they preferred iptacopan to their prior anti-C5 PNH treatments, with its oral administration and reduction in symptoms being key preference points.
These findings were consistent with interviews conducted with patients in APPLY-PNH and APPOINT-PNH, who most frequently identified the convenience of iptacopan’s oral administration and its efficacy as aspects they liked about the treatment.
These qualitative in-trial interviews provide valuable patient reported insights on PNH symptoms and treatment experience. Moreover, the findings from this research demonstrate that patients experienced meaningful improvement in PNH symptoms, particularly those related to fatigue, and that patients reported high levels of satisfaction with, and a preference for iptacopan due to its oral administration, convenience, and efficacy.

EFFECTS OF ORAL IPTACOPAN MONOTHERAPY, INCLUDING INCREASED PAROXYSMAL NOCTURNAL HEMOGLOBINURIA RED BLOOD CELL CLONE SIZE, ARE SUSTAINED IN ANTI-C5-TREATED PATIENTS WITH ANEMIA: FINAL APPLYPNH DATA

In the 24-week (wk) randomized period of the Phase III APPLY-PNH trial (NCT04558918), iptacopan (a first-inclass, oral factor B inhibitor) showed superiority vs C5 inhibitors and was well tolerated in anti-C5-treated PNH patients (pts) with persistent anemia.
The authors (Régis Peffault de Latour et al.) report final (48-wk) APPLY-PNH data, including PNH red blood cell (RBC) clone size and C3 fragment deposition, after a 24-wk extension period.
Adult PNH pts (receiving anti-C5 for ≥6 months; mean hemoglobin [Hb] <10 g/dL) were randomized to receive iptacopan monotherapy 200 mg twice daily or continue anti-C5 for 24 wks. In an optional 24-wk extension, pts in the iptacopan arm continued iptacopan; pts in the anti-C5 arm switched to iptacopan monotherapy.
95 pts entered the extension (iptacopan arm n=61/62; anti-C5-to-iptacopan arm n=34/35). In the iptacopan arm, improvements at Wk 24 were sustained at Wk 48, including increased Hb, normal/near-normal mean Hb and transfusion avoidance. Rapid improvements in these outcomes were seen in the anti-C5-to-iptacopan arm, reaching values comparable to the iptacopan arm. In the iptacopan and anti-C5-to-iptacopan arms, mean Hb at Wk 48 was 12.2 and 12.1 g/dL (SD 1.6 and 1.4; includes post-transfusion data), and 91.9% of pts (Wks 2–48) and 94.1% (Wks 26–48) achieved transfusion avoidance, respectively. The adjusted mean change from baseline (BL) to Wk 48 in Hb, Functional Assessment of Chronic Illness Therapy–Fatigue score and absolute reticulocyte count was +3.35 g/dL, +9.80 and −106.26 × 109/L in the iptacopan arm and +3.36 g/dL, +10.96 and −107.95 × 109/L in the anti-C5-to-iptacopan arm, respectively. In both arms, mean lactate dehydrogenase at Wk 48 wasconsistent with BL.
In the iptacopan arm, the increase from BL to Wk 24 in total PNH RBC (type II and type III) clone size was sustained to Wk 48 (Wk 48 mean 90.9%; mean change from BL 26.2%), as was a reduction in C3 fragment deposition on PNH RBCs (Wk 48 mean 1.97%; mean change from BL −16.1%; Figure). In the anti-C5-toiptacopan arm, PNH RBC clone size increased (Wk 48 mean 90.1%; mean change from Wk 24 to 48 30.3%) and C3 fragment deposition reduced (Wk 48 mean 0.12%; mean change from Wk 24 to 48 −16.9%) rapidly after switching treatment. 6/62 pts in the iptacopan arm had clinical breakthrough hemolysis (BTH; all mild or moderate) during 48 wks of therapy; in the anti-C5-to-iptacopan arm, clinical BTH occurred in 6/35 pts during 24 wks of anti-C5 and in one additional pt after switching to iptacopan. No BTH led to iptacopan discontinuation.

Three iptacopantreated pts had major adverse vascular events; none were considered treatment related. There were no deaths or treatment discontinuations due to treatment-emergent adverse events (TEAEs) with iptacopan. No serious hemolysis TEAEs or serious infections caused by N. meningitidis, S. pneumoniaeor H. influenzae occurred with iptacopan.
In APPLY-PNH, long-term iptacopan monotherapy led to durable responses and was well tolerated in anti-C5- treated PNH pts with anemia. Pts in the iptacopan arm had sustained improvements in several hematological and clinical parameters. An increase in PNH RBC clone size and decrease in C3 fragment deposition was maintained, indicating sustained control of intravascular hemolysis with resolution of extravascular hemolysis. Pts in the anti-C5-to-iptacopan arm had rapid improvements in outcomes after treatment switch. These data suggest that oral iptacopan monotherapy may be a practice-changing option for PNH pts with suboptimal response to anti-C5 therapy.

BREAKTHROUGH HEMOLYSIS IN PATIENTS WITH PAROXYSMAL NOCTURNAL HEMOGLOBINURIA TREATED WITH COMPLEMENT INHIBITORS: A MULTICENTER INTERNATIONAL STUDY

Dr. Bruno Fattizzo, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico and University of Milan, Milan, Italy

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare disease marked by complement-dependent intravascular hemolysis, thrombotic risk, and bone marrow failure. Complement inhibitors ameliorate anemia and abate thrombotic risk; however hemolytic exacerbations (breakthrough hemolysis, BTH) may occur due to insufficient effective plasma concentrations of the drug (pharmacokinetic BTH) or in case of complement activating triggers such as infections and surgery. The epidemiology, clinical grading, and management of BTH are not standardized. The aim of the study is to evaluate the frequency, clinical severity, and management of BTH in PNH.

Adult PNH patients actively followed at 9 tertiary centers in Italy and UK on treatment with anti-complement agents were retrospectively evaluated. Hematologic parameters and PNH clone size at diagnosis, type of inhibitor and relative response rates (categorized as per Risitano et al Front Immunol 2019) were collected. All hemolytic episodes were registered, including hematologic parameters, triggers, treatments administered, and outcome.
As shown in Table 1, 182 PNH patients with a median age of 37 years (range 18-88) were included; median clone size on granulocytes at diagnosis was 94% (5-99%), 43% of patients displayed moderate to severe anemia (Hb1.5 xULN), and 24% had experienced a thrombotic complication (all but 3 venous thrombosis, mainly in the splanchnic or pulmonary district). Most patients received eculizumab (89.5%) as first inhibitor, 68% required a second inhibitor (mainly ravulizumab, 69%), and 16% a third inhibitor (mainly danicopan as add on to anti-C5 or Iptacopan single agent, 26%).

During a median follow up of 6 (1-21) years on anti-complement therapy, 136 patients (75%) experienced a BTH episode, mostly due to infections (76%), and only 12% pharmacokinetic BTH in patients treated with eculizumab. Median number of BTH per patient was 1 (range 1-10), 26% of patients experiencing 2 or more episodes. All episodes were characterized by moderate to severe anemia and LDH increase >1.5 xULN; 45% of cases were treated with transfusions (mean of 3 RBCU/patient), 24% increased the dose or frequency of the complement inhibitor (26 anticipated eculizumab, 3 anticipated ravulizumab, 2 increased pegcetacoplan to 3 infusions/week and 1 added eculizumab for 2 doses), and 2 cases were managed with recombinant erythropoietin; 14% of patients were started on anticoagulant prophylaxis and 5 patients, not receiving prophylaxis, experienced breakthrough thrombosis (3 pulmonary embolisms and 2 DVT, 4%). Importantly, aggressive broad spectrum anti-microbial therapy was instituted in case of infections. Thereafter, most cases recovered to the basal Hb levels.

These preliminary data show that BTH complicates PNH course in more than 70% of patients, mainly due to infections as complement activating triggers. BTH are severe in most cases, requiring transfusions in nearly half of patients and increase dose/frequency of complement inhibitor in 24%. BTH was associated with breakthrough thrombosis in 4% of patients, highlighting the importance of evaluating anticoagulant prophylaxis that was instituted in a minority of patients only in this study.

UNDERSTANDING THE RELATIONSHIP BETWEEN HEMOGLOBIN, FATIGUE AND HEALTH-RELATED QUALITY OF LIFE FOR PATIENTS WITH PAROXYSMAL NOCTURNAL HEMOGLOBINURIA (PNH)

Jens Panse, University Hospital RWTH Aachen, Aachen, Germany; Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf, Aachen, Germany

PNH is a rare, chronic disease characterized by complement-mediated intravascular hemolysis and thrombosis and frequently associated with impaired bone marrow function. Fatigue, in its various presentations, is the most relevant clinical manifestation of PNH and generally impacts patients’ health-related quality of life (HRQoL). Current evidence to understand how hemoglobin (Hb) levels may impact fatigue and HRQoL for patients with PNH is limited.
The aim of this study was to quantify the relationship between Hb level and patient-reported outcomes utilizing the Functional Assessment of Chronic Illness Therapy – Fatigue (FACIT-Fatigue) and EQ5D-Visual Analogue Scale (VAS).
Data were drawn from the Adelphi PNH Disease Specific Programme™, a real-world, cross-sectional survey of physicians and their consulting patients with PNH in France, Germany, Italy, Spain, and Japan (January– November 2022). Physicians provided data regarding patient demographics, PNH signs/symptoms, and clinical values. The same patients completed the FACIT-Fatigue (13-item scale, score 0–52, general population mean [standard deviation (SD)] 43.5 [8.3]) and the EQ5D-VAS (score 0–100), a measure of health status; higher scores correspond to better outcomes. Linear regressions were performed to assess the relationship between FACIT-Fatigue and EQ5D-VAS vs each patient’s most recent Hb level: Regression A controlled for age and sex, while Regression B controlled for age, sex, most recent lactate dehydrogenase (LDH) level, and number of blood transfusions in the last 12 months.

Overall, 37 physicians provided data for 137 patients meeting the inclusion criteria. Median (interquartile range; IQR) age was 49.0 (35.0–64.5) years, 57% were male, and median (IQR) disease duration was 1.6 (0.7– 4.1) years. In this cohort, 69% were receiving complement C5 inhibitors for a median (IQR) duration of 1.1 (0.4–2.9) years. For 94% of patients, their Hb level was measured in the month prior to data collection, the mean (SD) Hb was 10.5 (1.3) g/dL, and 80% had Hb <12 g/dL. For patients’ most recent LDH level, 81% were below 1.5 × upper limit of normal (upper limit at 250 U/L). Physicians reported that 38% of patients had one or more blood transfusions within the 12 months prior to survey completion. According to patients, 87% experienced fatigue, with 45% describing their fatigue as moderate or severe. Mean (SD) FACIT-Fatigue score was 37.5 (9.3) and EQ5D-VAS score was 71.2 (15.7).

For every 1 g/dL increase in Hb, Regression A observed a 2.865 (95% confidence interval [CI]: 1.382─4.348) point increase (improvement) in FACIT-Fatigue score (P<0.001; n=137) and 1.742 (95% CI: 0.206─3.279 [P=0.027; n=131]) point increase in Regression B. For the same 1 g/dL increase in Hb, there was a 5.428 (95% CI: 2.977─7.880) point increase in EQ5D-VAS score (P<0.001; n=133) in Regression A and a 4.276 (95% CI: 1.961─6.591; P=0.001; n=127) point increase in Regression B.

Results from this study show that, after controlling for potential confounders, there is a statistically significant positive relationship between improvement in Hb levels and improvement in fatigue and general status. These findings highlight the importance of aiming to increase of Hb levels in PNH patients in order to improve their HRQoL, which could be achieved with newer therapies.