A randomized phase 3 trial of interferon-α vs hydroxyurea in polycythemia vera and essential thrombocythemia

Mascarenhas, John; Kosiorek, Heidi E.; Prchal, Josef T.; Berenzon, Dmitriy; Yacoub, Abdulraheem; Harrison, Claire; McMullin, Mary Frances; Vannucchi, Alessandro M.; Ewing, Joanne; Kiladjian, Jean‐Jacques; Mead, Adam J.; Winton, Elliott F.; Leibowitz, D; Stefano, Valerio De; Arcasoy, Murat O.; Kessler, Craig M.; Catchatourian, Rosalind; Rondelli, Damiano; Silver, Richard T.; Bacigalupo, Andrea; Nagler, Arnon; Kremyanskaya, Marina; Levine, Max F.; Ossa, Juan Arango; McGovern, Erin; Sandy, Lonette; Salama, Mohamed E.; Najfeld, Vesna; Tripodi, Joseph; Farnoud, Noushin; Penson, A.; Weinberg, Rona Singer; Price, Leah; Goldberg, Judith D.; Marchioli, Roberto; Tognoni, Gianni; Rampal, Raajit K.; Mesa, Ruben A.; Dueck, Amylou C.; Hoffman, Ronald; Barbui, Tiziano

doi:10.1182/blood.2021012743

Cited by 72 publications

(77 citation statements)

References 17 publications

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“…28 In addition, a recent study found that longer treatment with peg-IFN was more effective in normalizing levels of blood cells and reducing driver mutation burden, while hydroxycarbamide produced more histopathologic responses. 19 Our study shows for the first time that hydroxycarbamide and peg-IFN lead to alterations in activation-dependent granule markers in platelets. The mechanism of action of these drugs is still not fully understood.…”

Section: Discussionmentioning

confidence: 59%

“…However, it remains unknown if the risk of thromboembolic events differs between ET patients treated with different cytoreductive drugs. Some studies indicate that the risk may differ, 9,10,17,18 whereas a recent phase 3 study found no differences 19 . However, the study was not powered to detect a difference in the rate of thromboembolic events between hydroxycarbamide and peg‐IFN treated high‐risk ET patients 19 .…”

Section: Discussionmentioning

confidence: 96%

“…Some studies indicate that the risk may differ, 9,10,17,18 whereas a recent phase 3 study found no differences. 19 However, the study was not powered to detect a difference in the rate of thromboembolic events between hydroxycarbamide and peg-IFN treated high-risk ET patients. 19 It has been reported that peg-IFN is an effective treatment in ET patients refractory or intolerant to hydroxycarbamide therapy.…”

Section: Discussionmentioning

confidence: 99%

“…19 However, the study was not powered to detect a difference in the rate of thromboembolic events between hydroxycarbamide and peg-IFN treated high-risk ET patients. 19 It has been reported that peg-IFN is an effective treatment in ET patients refractory or intolerant to hydroxycarbamide therapy. 20 While no international consensus exists, younger ET patients (<40 years old) tend to receive peg-IFN rather than hydroxycarbamide as first line cytoreduction due to a theoretical increased risk of leukaemic transformation related to hydroxycarbamide.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, the difference in platelet markers between treatment groups likely also reflects the diverse influence on megakaryopoiesis by hydroxycarbamide and peg‐IFN and the fact that cytoreduction may not reverse all abnormal platelet markers 28 . In addition, a recent study found that longer treatment with peg‐IFN was more effective in normalizing levels of blood cells and reducing driver mutation burden, while hydroxycarbamide produced more histopathologic responses 19 . Our study shows for the first time that hydroxycarbamide and peg‐IFN lead to alterations in activation‐dependent granule markers in platelets.…”

Section: Discussionmentioning

confidence: 99%

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Cytoreductive treatment and association with platelet function and maturity in patients with essential thrombocythaemia

et al. 2022

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Summary Patients with essential thrombocythaemia (ET) have an increased risk of thromboembolic events, which may differ according to different cytoreductive drugs. We investigated the effect of cytoreductive treatment on platelet function and turnover in ET patients. Blood samples were obtained at 1 and 24 h after aspirin intake. Platelet function was evaluated by platelet aggregation and flow cytometry. Platelet turnover was assessed by immature platelet count, immature platelet fraction (IPF) and mean platelet volume (MPV). A total of 47 ET patients were included and grouped into 21 patients not receiving cytoreductive treatment, 15 patients receiving hydroxycarbamide and 11 patients receiving pegylated interferon alpha (peg‐IFN). Patients receiving peg‐IFN had significantly higher IPF and MPV than the other ET groups. Patients not receiving cytoreductive treatment had significantly higher platelet aggregation 24 h after aspirin intake than the other ET groups (p‐values from 0.03 to 0.0002). Patients receiving hydroxycarbamide had significantly higher expression of platelet granule makers, P‐selectin and CD63, than patients receiving peg‐IFN (p‐values ≤0.003). Cytoreduction provides more consistent platelet inhibition compared with no cytoreductive treatment. Moreover, peg‐IFN provides superior inhibition of platelet activation markers than hydroxycarbamide, which in part may explain differences in risk of thromboembolic events in ET patients.

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Section: Discussionmentioning

confidence: 59%

Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Cytoreductive treatment and association with platelet function and maturity in patients with essential thrombocythaemia

et al. 2022

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Diagnosis and Treatment of Polycythemia Vera

Tremblay,

Kremyanskaya,

Mascarenhas

et al. 2024

JAMA

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ImportancePolycythemia vera (PV), a myeloproliferative neoplasm characterized by an increased red blood cell mass and increased risk of thrombosis, affects approximately 65 000 people in the US, with an annual incidence of 0.5 to 4.0 cases per 100 000 persons.ObservationsErythrocytosis (hemoglobin &gt;16.5 mg/dL in men or &gt;16.0 mg/dL in women) is a required diagnostic criterion, although thrombocytosis (53%) and leukocytosis (49%) are common. Patients may have pruritus (33%), erythromelalgia (5.3%), transient visual changes (14%), and splenomegaly (36%) with abdominal discomfort. More than 95% of patients have a JAK2 gene variant, which helps distinguish PV from secondary causes of erythrocytosis, such as tobacco smoking or sleep apnea. Among 7 cohorts (1545 individuals), the median survival from diagnosis was 14.1 to 27.6 years. Prior to or at the time of PV diagnosis, arterial thrombosis occurred in 16% of patients and 7% had venous thrombotic events, which could involve unusual sites, such as splanchnic veins. PV is also associated with an increased bleeding risk, especially in patients with acquired von Willebrand disease, which can occur with extreme thrombocytosis (platelet count, ≥1000 × 109/L). All patients with PV should receive therapeutic phlebotomy (goal hematocrit, &lt;45%) and low-dose aspirin (if no contraindications). Patients who are at higher risk of thrombosis include those aged 60 years or older or with a prior thrombosis. These patients and those with persistent PV symptoms may benefit from cytoreductive therapy with hydroxyurea or interferon to lower thrombosis risk and decrease symptoms. Ruxolitinib is a Janus kinase inhibitor that can alleviate pruritus and decrease splenomegaly in patients who are intolerant of or resistant to hydroxyurea. About 12.7% of patients with PV develop myelofibrosis and 6.8% develop acute myeloid leukemia.Conclusions and RelevancePV is a myeloproliferative neoplasm characterized by erythrocytosis and is almost universally associated with a JAK2 gene variant. PV is associated with an increased risk of arterial and venous thrombosis, hemorrhage, myelofibrosis, and acute myeloid leukemia. To decrease the risk of thrombosis, all patients with PV should be treated with aspirin and therapeutic phlebotomy to maintain a hematocrit of less than 45%. Cytoreductive therapies, such as hydroxyurea or interferon, are recommended for patients at high risk of thrombosis.

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Patient-Reported Outcomes in Phase 3 Clinical Trials for Blood Cancers: A Systematic Review

Patel,

Ivanov,

Jocelyn

et al. 2024

JAMA Netw Open

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ImportancePublished research suggests that patient-reported outcomes (PROs) are neither commonly collected nor reported in randomized clinical trials (RCTs) for solid tumors. Little is known about these practices in RCTs for hematological malignant neoplasms.ObjectiveTo evaluate the prevalence of PROs as prespecified end points in RCTs of hematological malignant neoplasms, and to assess reporting of PROs in associated trial publications.Evidence ReviewAll issues of 8 journals known for publishing high-impact RCTs (NEJM, Lancet, Lancet Hematology, Lancet Oncology, Journal of Clinical Oncology, Blood, JAMA, and JAMA Oncology) between January 1, 2018, and December 13, 2022, were searched for primary publications of therapeutic phase 3 trials for adults with hematological malignant neoplasms. Studies that evaluated pretransplant conditioning regimens, graft-vs-host disease treatment, or radiotherapy as experimental treatment were excluded. Data regarding trial characteristics and PROs were extracted from manuscripts and trial protocols. Univariable analyses assessed associations between trial characteristics and PRO collection or reporting.FindingsNinety RCTs were eligible for analysis. PROs were an end point in 66 (73%) trials: in 1 trial (1%) as a primary end point, in 50 (56%) as a secondary end point, and in 15 (17%) as an exploratory end point. PRO data were reported in 26 of 66 primary publications (39%): outcomes were unchanged in 18 and improved in 8, with none reporting worse PROs with experimental treatment. Trials sponsored by for-profit entities were more likely to include PROs as an end point (49 of 55 [89%] vs 17 of 35 [49%]; P &lt; .001) but were not significantly more likely to report PRO data (20 of 49 [41%] vs 6 of 17 [35%]; P = .69). Compared with trials involving lymphoma (18 of 29 [62%]) or leukemia or myelodysplastic syndrome (18 of 28 [64%]), those involving plasma cell disorders or multiple myeloma (27 of 30 [90%]) or myeloproliferative neoplasms (3 of 3 [100%]) were more likely to include PROs as an end point (P = .03). Similarly, compared with trials involving lymphoma (3 of 18 [17%]) or leukemia or myelodysplastic syndrome (5 of 18 [28%]), those involving plasma cell disorders or multiple myeloma (16 of 27 [59%]) or myeloproliferative neoplasms (2 of 3 [67%]) were more likely to report PROs in the primary publication (P = .01).Conclusions and RelevanceIn this systematic review, almost 3 of every 4 therapeutic RCTs for blood cancers collected PRO data; however, only 1 RCT included PROs as a primary end point. Moreover, most did not report resulting PRO data in the primary publication and when reported, PROs were either better or unchanged, raising concern for publication bias. This analysis suggests a critical gap in dissemination of data on the lived experiences of patients enrolled in RCTs for hematological malignant neoplasms.

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A randomized phase 3 trial of interferon-α vs hydroxyurea in polycythemia vera and essential thrombocythemia

Cited by 72 publications

References 17 publications

Cytoreductive treatment and association with platelet function and maturity in patients with essential thrombocythaemia

Cytoreductive treatment and association with platelet function and maturity in patients with essential thrombocythaemia

Diagnosis and Treatment of Polycythemia Vera

Patient-Reported Outcomes in Phase 3 Clinical Trials for Blood Cancers: A Systematic Review

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