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Myeloid/Lymphoid Neoplasms (MLNs)

MLNs with FGFR1 rearrangement are rare blood cancers1

  • Also known as 8p11 myeloproliferative syndrome1
  • Classified by the World Health Organization as an MLN with eosinophilia and FGFR1 rearrangement1,2
Icon of the chromosome 8p11 locus
Icon of the chromosome 8p11 locus
Translocation drives constitutive FGFR1 activity1

Translocation involving the FGFR1 gene located at the chromosome 8p11 locus results in a novel fusion protein and constitutive activation of the FGFR1 tyrosine kinase.

Diagnosis may be difficult due to a diverse range of presentations1

Demographic and other information on patients with MLNs with FGFR1 rearrangement comes from small case reviews3,4

  • Median age at diagnosis is 46 years (range, 0-87 years)4
  • On exam, patients commonly have lymphadenopathy and organomegaly (splenomegaly or hepatomegaly)1,5
  • Symptom burden may vary:
    • Up to 20% of patients do not have symptoms at the time of diagnosis and may be identified during routine laboratory testing5
    • Symptomatic patients may experience symptoms found in other blood cancers such as fatigue (35%), night sweats (28%), weight loss (18%), or fever (13%)5-7
  • The disease is generally associated with an aggressive clinical course8
    • Roughly 15% of patients present with acute leukemia3
    • The disease may show rapid progression of chronic-phase disease to blast-phase/secondary acute leukemia8
  • In a literature review of patients with MLNs with FGFR1 rearrangement, the 1-year overall survival rate from diagnosis in 41 patients was 43.1% (95% CI, 26.8-58.4)4

Diagnostic criteria for MLNs with FGFR1 rearrangement2,9,10

Chronic myeloid neoplasm, usually a myeloproliferative or myelodysplastic/ myeloproliferative neoplasm with eosinophilia, neutrophilia, or monocytosis

OR
OR

T-or B-acute lymphoblastic leukemia/lymphoma, acute myeloid leukemia, blast-phase myeloproliferative neoplasm, or mixed-phenotype acute leukemia (usually associated with peripheral blood or bone marrow eosinophilia)

AND
AND

Presence of t(8;13) (p11;q12) or variant 8p11 translocation leading to FGFR1 rearrangement in myeloid cells, lymphoblasts, or both

Confirm diagnosis through conventional cytogenetics and fluorescence in situ hybridization (FISH)8

  • An FDA-approved test for detection of FGFR1 rearrangement in patients with relapsed or refractory MLNs for selecting patients for treatment with PEMAZYRE is not available11
  • During initial evaluation, conventional cytogenetics can identify translocations, and FISH testing using FGFR1 break-apart probes can confirm FGFR1 rearrangement8
    • Eosinophilia has been noted in up to 85% of cases reported in the literature5
  • FGFR1 is not part of standard testing panels and in some cases must be specifically ordered5

CI, confidence interval; FDA, Food and Drug Administration; FGFR, fibroblast growth factor receptor.

References

  1. Li T, Zhang G, Zhang X, et al. The 8p11 myeloproliferative syndrome: genotypic and phenotypic classification and targeted therapy. Front Oncol. 2022;12:1015792.
  2. Arber DA, Orazi A, Hasserjian RP, et al. International Consensus Classification of Myeloid Neoplasms and Acute Leukemias: integrating morphologic, clinical, and genomic data. Blood. 2022;140(11):1200-1228.
  3. Vega F, Medeiros LJ, Bueso-Ramos CE, et al. Hematolymphoid neoplasms associated with rearrangements of PDGFRA, PDGFRB, and FGFR1Am J Clin Pathol. 2015;144(3):377-392.
  4. Umino K, Fujiwara S-I, Ikeda T, et al. Clinical outcomes of myeloid/lymphoid neoplasms with fibroblast growth factor receptor-1 (FGFR1) rearrangement. Hematology. 2018;23(8):470-477.
  5. Jackson CC, Medeiros LJ, Miranda RN. 8p11 myeloproliferative syndrome: a review. Hum Pathol. 2010;41(4):461-476.
  6. Leukemia & Lymphoma Society. Non-Hodgkin lymphoma: signs and symptoms. https://www.lls.org/lymphoma/non-hodgkin-lymphoma/signs-and-symptoms. Accessed October 14, 2024.
  7. American Society of Hematology. Leukemia. https://hematology.org/education/patients/blood-cancers/leukemia. Accessed October 14, 2024.
  8. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Myeloid/Lymphoid Neoplasms with Eosinophilia and Tyrosine Kinase Gene Fusions V.2.2024. ©National Comprehensive Cancer Network, Inc. 2024. All rights reserved. Accessed July 31, 2024. To view the most recent and complete version of the guideline, go online to NCCN.org.
  9. Khoury JD, Solary E, Abla O, et al. The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms. Leukemia. 2022;36(7):1703-1719.
  10. Shomali W, Colucci P, George TI. Comprehensive response criteria for myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions: a proposal from the MLN International Working Group. Leukemia. 2023;37(5):981-987.
  11. PEMAZYRE Prescribing Information. Wilmington, DE: Incyte Corporation.

Indications and Usage

PEMAZYRE® is indicated for the treatment of adults with relapsed or refractory myeloid/lymphoid neoplasms (MLNs) with fibroblast growth factor receptor 1 (FGFR1) rearrangement.

Important Safety Information

Ocular Toxicity

Retinal Pigment Epithelial Detachment (RPED): PEMAZYRE can cause RPED, which may cause symptoms such as blurred vision, visual floaters, or photopsia. Clinical trials of PEMAZYRE did not conduct routine monitoring including optical coherence tomography (OCT) to detect asymptomatic RPED; therefore, the incidence of asymptomatic RPED with PEMAZYRE is unknown.

Among 635 patients who received a starting dose of PEMAZYRE 13.5 mg across clinical trials, RPED occurred in 11% of patients, including Grade 3-4 RPED in 1.3%. The median time to first onset of RPED was 56 days. RPED led to dose interruption of PEMAZYRE in 3.1% of patients, and dose reduction and permanent discontinuation in 1.3% and in 0.2% of patients, respectively. RPED resolved or improved to Grade 1 levels in 76% of patients who required dosage modification of PEMAZYRE for RPED.

Perform a comprehensive ophthalmological examination including OCT prior to initiation of PEMAZYRE and every 2 months for the first 6 months and every 3 months thereafter during treatment. For onset of visual symptoms, refer patients for ophthalmologic evaluation urgently, with follow-up every 3 weeks until resolution or discontinuation of PEMAZYRE. Modify the dose or permanently discontinue PEMAZYRE as recommended in the prescribing information for PEMAZYRE.

Dry Eye: Among 635 patients who received a starting dose of PEMAZYRE 13.5 mg across clinical trials, dry eye occurred in 31% of patients, including Grade 3-4 in 1.6% of patients. Treat patients with ocular demulcents as needed.

Hyperphosphatemia and Soft Tissue Mineralization

PEMAZYRE can cause hyperphosphatemia leading to soft tissue mineralization, cutaneous calcification, calcinosis, and non-uremic calciphylaxis. Increases in phosphate levels are a pharmacodynamic effect of PEMAZYRE. Among 635 patients who received a starting dose of PEMAZYRE 13.5 mg across clinical trials, hyperphosphatemia was reported in 93% of patients based on laboratory values above the upper limit of normal. The median time to onset of hyperphosphatemia was 8 days (range 1-169). Phosphate lowering therapy was required in 33% of patients receiving PEMAZYRE.

Monitor for hyperphosphatemia and initiate a low phosphate diet when serum phosphate level is >5.5 mg/dL. For serum phosphate levels >7 mg/dL, initiate phosphate lowering therapy and withhold, reduce the dose, or permanently discontinue PEMAZYRE based on duration and severity of hyperphosphatemia as recommended in the prescribing information.

Embryo-Fetal Toxicity

Based on findings in an animal study and its mechanism of action, PEMAZYRE can cause fetal harm when administered to a pregnant woman. Oral administration of pemigatinib to pregnant rats during the period of organogenesis caused fetal malformations, fetal growth retardation, and embryo-fetal death at maternal exposures lower than the human exposure based on area under the curve (AUC) at the clinical dose of 13.5 mg.

Advise pregnant women of the potential risk to the fetus. Advise female patients of reproductive potential to use effective contraception during treatment with PEMAZYRE and for 1 week after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with PEMAZYRE and for 1 week after the last dose.

Adverse Reactions: Myeloid/Lymphoid Neoplasms with FGFR1 Rearrangement

Serious adverse reactions occurred in 53% of patients receiving PEMAZYRE at all dosages (n=34). Serious adverse reactions in > 5% of patients included acute kidney injury. Fatal adverse reactions occurred in 9% of patients who received PEMAZYRE, including acute kidney injury, multiple organ dysfunction syndrome, and malignant neoplasm progression, occurring in one patient each.

Permanent discontinuation due to an adverse reaction occurred in 12% of patients who received PEMAZYRE at all dosages. Adverse reactions requiring permanent discontinuation included cardiac failure, multiple organ dysfunction syndrome, blood alkaline phosphatase increase, and calciphylaxis. In patients who started treatment on the recommended dosage (n = 20), adverse reactions requiring dosage interruption of PEMAZYRE occurred in 80% of patients. Adverse reactions which required dosage interruption in > 2 patients treated at the recommended dosage included nail toxicities (20%) and hyperphosphatemia (15%).

Dose reductions of PEMAZYRE due to an adverse reaction occurred in 80% of patients who started treatment on the recommended dosage. Adverse reactions requiring dose reductions occurring in > 2 patients were nail toxicities (20%), hyperphosphatemia (20%), and alopecia (15%).

Clinically relevant adverse reactions occurring in ≤10% of patients included fractures (2.1%). In all patients treated with pemigatinib, 0.5% experienced pathologic fractures (which included patients with and without cholangiocarcinoma [N = 635]). Soft tissue mineralization, including cutaneous calcification, calcinosis, and non-uremic calciphylaxis associated with hyperphosphatemia were observed with PEMAZYRE treatment.

Within the first 21-day cycle of PEMAZYRE dosing, serum creatinine increased (mean increase of 0.2 mg/dL) and reached steady state by Day 8, and then decreased during the 7 days off therapy. Consider alternative markers of renal function if persistent elevations in serum creatinine are observed.

The most common (≥ 20%) adverse reactions were hyperphosphatemia (74%), nail toxicity (62%), alopecia (59%), stomatitis (53%), diarrhea (50%), dry eye (50%), fatigue (44%), rash (35%), abdominal pain (35%), anemia (35%), constipation (32%), dry mouth (32%), epistaxis (29%), retinal pigment epithelial detachment (26%), extremity pain (26%), decreased appetite (24%), dry skin (24%), dyspepsia (24%), back pain (24%), nausea (21%), blurred vision (21%), peripheral edema (21%), and dizziness (21%).

Drug Interactions

Avoid concomitant use of strong and moderate CYP3A inhibitors with PEMAZYRE. Reduce the dose of PEMAZYRE if concomitant use with a strong or moderate CYP3A inhibitor cannot be avoided. Avoid concomitant use of strong and moderate CYP3A inducers with PEMAZYRE.

Special Populations

Advise lactating women not to breastfeed during treatment with PEMAZYRE and for 1 week after the last dose.

Reduce the recommended dose of PEMAZYRE for patients with severe renal impairment as described in the prescribing information.

Reduce the recommended dose of PEMAZYRE for patients with severe hepatic impairment as described in the prescribing information.