Myeloproliferative neoplasms with clinically relevant paroxysmal nocturnal hemoglobinuria: clinical correlations and outcomes

Myeloproliferative neoplasms (MPN) are clonal hematopoietic stem cell disorders driven by mutations in JAK2, CALR, or MPL, and include polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF).¹ Clinical manifestations include thrombohemorrhagic complications and risk of leukemic or fibrotic progression.² Paroxysmal nocturnal hemoglobinuria (PNH) is also an acquired hematopoietic stem cell disorder caused by PIGA mutations. Clinical manifestations include complement-mediated intravascular hemolysis and thrombosis.³ PNH is typically associated with aplastic anemia (AA) and myelodysplastic syndrome (MDS).^3,4 Although the co-existence of MPN and PNH is rare,^4-8 both entities are associated with anemia and increased thrombotic risk.^2,3 The main objectives of the current study were to characterize the clinical phenotype and evaluate treatment outcomes, including response to complement inhibition in patients with MPN and PNH.

A Mayo Clinic enterprise-wide database search was conducted to identify patients with MPN and concomitant PNH following institutional review board approval. The requirement for informed consent was waived by the ethics committee. Between January 2000 and June 2025, 8 patients had a diagnosis of MPN according to the International Consensus Classification, and treatment-requiring PNH. Evaluation for PNH was performed in MPN patients with intravascular hemolysis or splanchnic venous thrombosis. Clinical features, including hemolysis and thrombosis, and therapeutic interventions were recorded.

The study cohort included 8 patients (median age 65 years; 88% males) with MPN (5 with PMF, 2 ET, 1 post-ET MF) in whom PNH was diagnosed concomitantly (N=3), or at a median of eight years (range 2-14) after MPN diagnosis (N=5). In 7 of 8 patients (87%), workup for PNH was instigated by hemolytic anemia, while in one patient (13%), it was prompted by splanchnic vein thrombosis. MPN driver mutations were evaluated in 6 cases: JAK2 (N=2) and CALR (Type 1, N=3; Type 2, N=1); an additional case was JAK2 negative. Next-generation sequencing was performed in 5 patients and identified additional mutations in ASXL1, ZRSR2, and SF3B1 in one case each. Cytogenetics data were available for all except one patient, and only one (14%) showed an abnormal but favorable karyotype. PNH clone size was evaluated in 7 cases (median 3.92%; range 0.02-10.96%) in red blood cells (RBC), 28.8% (range 6.1-91.2%) in granulocytes, and 60.1% (6.6-98.8%) in monocytes. Table 1 outlines laboratory values on presentation; information on the clinical characteristics and course for each of these cases are summarized in Tables 2 and 3, and are discussed below. Patient #1, a 67-year-old male, was diagnosed with concomitant PNH and PMF following hemolytic anemia workup and was initiated on eculizumab; during follow-up of five years, hemoglobin was steady at 12 g/dL.

Patient #2, a 63-year-old female, presented with hemolytic anemia and was diagnosed with CALR and ASXL1-mutated PMF and concomitant PNH with a granulocyte clone size of 28.8%. She had a baseline hemoglobin of 10.5 g/dL and received ruxolitinib for symptomatic splenomegaly. However, a month later, eculizumab was initiated due to ongoing hemolysis requiring transfusions. During 8.5 years of follow-up, she remained transfusion-dependent, despite a switch in treatment from ruxolitinib to pacritinib.

Patient #3, a 70-year-old male with CALR-mutated ET, was diagnosed with PNH, ten years after MPN diagnosis, following workup for hemolysis. PNH clone in granulocytes was 63.9% and baseline hemoglobin at PNH diagnosis was 8.6 g/dL. He received eculizumab without improvement in anemia. Thereafter, due to concern for disease evolution to MDS, he underwent allogeneic stem cell transplantation (allo-SCT). Five months after transplant, he had recurrence of PNH and received 2 donor lymphocyte infusions (DLI), and eculizumab was reinitiated which led to eradication of the PNH clone. At ten months post transplant, he developed deep venous thrombosis (DVT), which was managed with anticoagulation. In addition, during the 8-year follow-up, he developed chronic graft-versus-host disease (GvHD) with ocular, skin, and hepatic involvement.

Patient #4, a 68-year-old male with CALR-mutated MF, experienced multiple recurrent venous thrombotic events, involving portal and mesenteric veins, as well as pulmonary embolism, prompting PNH workup 14 years after MPN diagnosis. PNH clone in granulocytes was 14.65%. A year prior to PNH diagnosis, hemoglobin was 4 g/dL due to gastrointestinal bleed associated with massive splenomegaly, for which he underwent splenectomy. Over the next two years, despite use of eculizumab and low-molecular weight heparin, he had recurrent thromboses, involving infrarenal inferior vena cava (IVC), bilateral common iliac veins, suprarenal and intrahepatic IVC, and middle hepatic vein, and remained transfusion-dependent.

Patient #5, a 69-year-old male with CALR-mutated postET MF developed hemolytic anemia (baseline hemoglobin 9 g/dL), two years after MPN diagnosis. PNH clone was 22.58% in granulocytes. He received eculizumab without improvement in hemolysis and underwent allo-SCT 1-year post diagnosis. While he achieved remission from the MF and PNH standpoint, post-transplant course was complicated by end-stage renal disease.

Patient #6, a 76-year-old male with JAK2-mutated ET, developed progressive anemia (hemoglobin 8 g/dL) eight years later. PNH clone in granulocytes was 91.19%. Despite optimal eculizumab trough levels (>350 mcg/mL) and <10% activity on complement inhibition assay, hemolysis was uncontrolled requiring multiple therapies: ravulizumab, followed by iptacopan, and later transitioned to dual complement blockade with ravulizumab and danicopan. Patient #7, a 66-year-old male with JAK2-negative PMF presented with hemolysis three years after diagnosis, at which time a 6.1% PNH clone in granulocytes was noted. Over the next five years, he received erythropoiesis-stimulating agents (ESA), danazol, thalidomide, and prednisone, which failed to alleviate transfusion-dependent anemia. Thereafter, he received eculizumab for 2.5 years and ruxolitinib without improvement in hemoglobin. Unfortunately, he died due to sepsis.

Table 1.Baseline presenting features at diagnosis of myeloproliferative neoplasm and paroxysmal nocturnal hemoglobinuria.

Table 2.Clinical and molecular characteristics of patients with concomitant myeloproliferative neoplasm and paroxysmal nocturnal hemoglobinuria.

Patient #8, a 67-year-old male was referred for transfusion-dependent anemia and was diagnosed with concomitant JAK2-mutated PMF and PNH, with a clone size of 90.6% in granulocytes. He was initially treated with eculizumab and later switched to ravulizumab due to treatment failure. He subsequently underwent allo-SCT; over the next five years, his post-transplant course was complicated by acute skin GvHD. At last follow-up, he remains in remission from PMF and PNH.

Overall, complement inhibition was the mainstay for PNH management with all patients receiving either eculizumab (N=7) or ravulizumab (N=2); 5 of these received eculizumab as monotherapy. Only one of 8 patients achieved disease control using complement inhibition alone. Three patients underwent allo-SCT, of whom 2 achieved sustained remission with follow-up exceeding five years, while the third patient experienced PNH recurrence five months post transplant. Among patients treated with complement inhibition therapy but not transplanted, 4 of 5 (80%) remained transfusion dependent at last follow-up. Treatment for MPN included hydroxyurea (N=3), ruxolitinib (N=3), pacritinib (N=1), and ESA (N=3). Additionally, one patient received anticoagulation alone and 2 were treated with a combination of antiplatelet and anticoagulation therapies.

Table 3.Clinical course and treatment approaches in patients with concomitant myeloproliferative neoplasm and paroxysmal nocturnal hemoglobinuria.

During a median follow-up of 8.4 years (range 5-19), 2 patients (25%) experienced venous thrombosis, and one patient (13%) had progression to MDS. Three patients (38%) died, including 2 from sepsis. The incidence rate of thrombosis was 24 events per 100 person-years. Recurrent thrombosis was observed in a 68-year-old male with CALR-mutated MF and PNH clone size of 14.65% in granulocytes, with history of portal vein thrombosis. Despite treatment with eculizumab and LMWH, he developed thromboses involving the IVC, common iliac, and hepatic veins. The second thrombotic event occurred in a patient who developed DVT while in remission and not receiving anticoagulation. A recent study showed presence of PNH clones in 3 of 119 (2.5%) MPN patients.⁹ The current study represents one of the largest series of patients with MPN and PNH. It reveals a predominance of MF patients, particularly with CALR mutations. Sutra del Galy et al.⁵ described 20 patients with PNH and myeloid neoplasms, including 8 with MPN (5 JAK2, 2 CALR). The study reported thrombosis in 50% and hemolysis in all patients. Eighty percent of the patients were transfusion-dependent, and despite treatment with eculizumab in 13 patients, none achieved transfusion independence. By contrast, 4 of 5 patients who underwent transplantation were alive in remission. Additionally, several case reports have described co-existence of PNH and MPN including JAK2-negative ET (N=4), CALR-mutated ET (N=6), PV (N=7), and CALR-mutated post-ET MF (N=8).

Paroxysmal nocturnal hemoglobinuria should be suspected in MPN patients with active intravascular hemolysis or splanchnic venous thrombosis. However, the limitations of hemolysis evaluation in the context of MPN should be noted.¹⁰ Although complement inhibition was the first-line treatment for PNH, its efficacy was suboptimal, with only 20% achieving transfusion independence. By contrast, among 3 patients who underwent transplant, only 2 achieved durable remission, while the third patient experienced recurrence of PNH, which required DLI and re-treatment with eculizumab before successful remission was achieved. Given the modest response to complement inhibition, allo-SCT should be considered sooner rather than later. Taken together, these findings highlight the therapeutic challenges in managing patients with concomitant MPN and PNH.

Footnotes

• Received September 1, 2025
• Accepted November 19, 2025

Correspondence

N. GANGAT - gangat.naseema@mayo.edu

Disclosures

NG has served on the advisory board for Agios and DISC medicine. MP received research funding from Kura Oncology, Stemline Therapeutics, Epigenetix, Solutherapeutics, and Polaris, and has served on the advisory board for AstraZeneca and SOBI Pharmaceuticals. All of the other authors have no conflicts of interest to disclose.

Contributions