Case Report: Priapism as The Clinical Presenting Feature of Chronic Myeloid Leukemia: Case Report and 20-Year Literature Review

Priapism in chronic myeloid leukemia (CML) appears to be an infrequent manifestation as well as a crucial emergency. Here, we report an 18-year-old male presenting with a persistent erection of the penis for 20 days. We evaluated and compared the reported cases within 20 years discussing the management of priapism in CML. Cytoreductive therapy followed by leukapheresis, the administration of tyrosine kinase inhibitor, and intra-cavernosal blood aspiration may resolve the symptoms of priapism. Early intervention for cytoreduction and aspiration are the pivotal keys to successfully impeding the complications.


Introduction
Priapism is a urological emergency due to persistence of an erection lasting more than 4 hours, whether or not it is related to sexual influence. 1 Priapism is a rare condition with an incidence of 1-5 cases per 100,000 people per year.Penile erection in priapism is regularly painless.There are two types of priapism, which are low-flow priapism and high-flow priapism.Low-flow priapism is provoked by a pathological condition of low venous blood flow causing stasis in the penile vessels.This condition is an emergency condition that can result in cell damage and fibrosis, thus it often requires immediate therapy.Meanwhile, high-flow priapism is caused by increased blood flow to the sinusoid arteries without offsetting the flow to the veins.[4] Priapism accounts for 20% of the hematological abnormalities while 1-5% of priapism are due to leukemia.The theory behind a priapism is the dysregulation of nitric oxide (NO) in penile vascularization.This occurs due to changes in NO synthase enzyme activity which decrease NO production by the corpora cavernosa.This ischemic condition induces platelet aggregation, thrombus, and tissue damage.Decreased NO interferes with smooth muscle tone and generates the priapism.Hyperviscosity conditions due to leukocytosis and adenosine-opiorphins abnormalities is also involved in this condition. 1rrently, the approach to treat CML patients with priapism uses a combination of systemic therapy (chemotherapy with hydroxyurea or tyrosine kinase inhibitors and leukapheresis) and local intracavernosal therapy.Some cases with late manifestations cause erectile dysfunction, gangrene and penile abscess. 5This case report and review aims to discuss the clinical characteristics and outcomes of CML patients who experience priapism.

Case
An 18-year-old unmarried male student, presented at the ER complaining of persistent erection of the penis.The patient complained of persistent erected penis for 20 days before admission.There was no phase without an erection in between.Previously, there was neither history of trauma to sexual stimulation, nor consumption of certain drugs.The patient also complained of mild genital pain along with the onset of erection.There were no complaints about discoloration of the penis; becoming reddish, bluish, or pale, also there was no numbness.The patient could urinate normally (see Figure 1).
The patient complained of tinnitus in his right and left ears for 15 days accompanied by blurred vision.The patient also felt that his left side of stomach was slowly enlarging for 5 months.There was no bleeding and fever.Before coming to the

REVISED Amendments from Version 1
As advised by the reviewer, we have simplified the title, paid attention to unclear sentences, removed and revised them.We also have added one recommended reference to our discussion.
ER, the patient was hospitalized at the regional hospital and received a blood transfusion and was diagnosed with a blood disorder.
The patient underwent leukapheresis once per day (three times since initial admission) with gradual improvement.Unfortunately, on the fourth day of treatment the patient felt a penis erection again with pain on a scale of 0-5.Local examination of the genitalia showed a maximal erected penis, with no discoloration indicative of hyperemia, cyanosis, or pallor.Blood gas analysis showed pH 6.95, pCO 2 64 mmHg, HCO 3 14 mEQ/L, BE -18 unit.We concluded that the patient had ischemic priapism.Therefore, the patient underwent intracavernous aspiration producing 150 mL blood.Not long after that, the patient's penis returned to an erection with bleeding from the puncture wound.We then decided to give leukapheresis to the patient.
On the eighth day of treatment, the erection improved with pain scale of 1. Quantitative BCR-ABL examination showed a positive result of 65%, thus the administration of hydroxyurea was stopped and replaced by imatinib 400 mg once daily at night.On the twelfth day of treatment, the erection completely resolved and the patient was successfully discharged from the hospital.

Discussion
This review presents data on patients who have priapism due to CML (see Table 1).Priapism occurred in the age ranging from 9-53.Patients usually had episodes of priapism for 18 h to 7 days.Not all patients with priapism showed a typical clinical examination of CML in the form of splenomegaly, but all of these patients had a hyperleukocytosis profile with a leukocyte count >200,000 cells/mm 3 .Some of them are equipped with data of peripheral blood smear with excessive blast and identification of BCR-ABL gene.A study by Minckler et al. was the only one reporting a resolved erection with a cold shower, whilst most other cases needed medical intervention. 6Although the duration of symptoms varied, four cases reported complications following an episode of priapism.Patients with unfavorable outcomes once received hydroxyurea, imatinib but failed to undergo urological emergency therapy such as intra-cavernosa aspiration, surgical intervention, and embolization.
The patient in our study was 18 years old.However, based on the literature, patients in every age group are at risk of developing priapism.There are two peaks in the age distribution that tend to experience this condition.The peak in earlier age is between 5 and 10 years, especially in patients with sickle cell disease.Meanwhile, the second peak is at sexually active phase between 20 and 50 years.Apart from hypercoagulability, this condition may also be related to the abuse of erectile drugs. 7story and physical examination are important when encountering cases of priapism.Laboratory tests are required to check for impaired coagulation and serum electrolytes.Some patients who are at high risk for priapism include users of intracorporal injection therapy for erectile dysfunction, coagulation disorders such as sickle cell disease and CML. 2,4In CML, hyperleukocytosis is thought to be the prime cause of priapism.The main mechanism is the aggregation of leukemic cells in the corpora cavernosa and dorsal veins of the penis.Other than that, mechanical pressure in the abdominal veins due to the enlargement of the spleen might also increase the risk. 1 The data needed in the management of patients with this case are erection duration, pain scale, trauma, complete blood count, peripheral blood smear, penile blood gas analysis, bone marrow and polymerase chain reaction for BCR-ABL1 if necessary. 1,2,4In CML, the most common type of priapism is the ischemic one (veno-occlusive).Patients usually complain of painful, rigid erection, with reduced to no cavernous blood flow at all.Priapism that lasts for more than 4 hours indicates a compartment syndrome and may require emergent medical intervention. 8e American Urological Association recommends that systemic treatment of an underlying disorder should not be the only one therapy for ischemic priapism.In this case, the patient had an erectile episode since 20 days before the admission.This phenomenon was likely due to the compartment syndrome, hence the intra-cavernous aspiration was required.The intra-cavernous aspiration procedure can be accomplished by giving the anesthetic injection first under the symphysis pubis.The penis is tied with a tourniquet followed by insertion of a 16-18-Gauge bivalve intravenous catheter into the corpus cavernosum.When the two corpora are fused, aspiration of 20-30 mL of blood can be undertaken.This procedure has 30% chances of success. 8,9stemic therapy is often used to reduce hyperviscosity is cytoreductive therapy such as high-dose hydroxycarbamide and tyrosine kinase inhibitors (TKI) with or without apheresis procedures.Hydroxycarbamide can be given 2-6 grams divided into four doses per day.This can reduce leukocytes by almost 60% in 24-48 h.In addition, TKI, such as imatinib, can be administered as soon as the diagnosis is confirmed.The recommended dose of imatinib is 400 mg once daily in the chronic phase, 600-800 mg once daily in the accelerated phase, and 800 mg once daily in a blast crisis. 9Generally, IRIS study describes the effectiveness of imatinib therapy for complete hematological response (CHR), major cytogenetic response (McyR) and complete cytogenetic response (CcyR). 4ukapheresis can promote a rapid decrease in intravascular leukemic cells, improve tissue perfusion and prevent leukostasis (generally show pulmonary and central nervous system manifestations).Once leukapheresis is given, it possibly can reduce the leukocyte count by 30-60%.However, compared to the chemotherapy, several previous studies have shown that this procedure had high all-cause mortality.According to 2016 apheresis guidelines, category 2 (secondline therapy) is recommended for grade 1B of acute myeloid leukemia (strong recommendation, moderate quality evidence), while category 3 (unclear role of apahresis) is recommended for acute lymphoblastic leukemia cases grade 2C (weak recommendation, low quality evidence).In this guideline, leukapheresis is not recommended for chronic myeloid leukemia. 10Several cases of priapism in this case review reported a successful combination of leukapheresis with systemic oral CML therapy.A study by Rojas et al. was the only one reporting a failed leukapheresis.
This case report and review presents a comparative presentation of patient characteristics, clinical characteristics of CML, laboratory profile, and therapeutic intervention for CML with priapism.Clinical presentation and early intervention are pivotal keys to achieve favorable outcome and prevent complications.Systemic intervention combined with intraurethral therapy may add the success rate (see Figure 2).
Eventually, further discussion and study on other causes of priapism is essential as a meta-analysis stated that priapism might also be related to lymphoproliferative disorders. 32

Ritu Gupta
Laboratory Oncology Unit, Dr B.R. Ambedkar IRCH, All India Institute of Medical Sciences (AIIMS), New Delhi, New Delhi, Delhi, India Priapism is an unusual complication of hematological malignancy with hyperleukocytosis and may be the presenting feature, especially in chronic leukemia as observed in this case.
The authors have described the clinical features, investigations, and management of the index case and reviewed the literature on the association of priapism with CML.
I have a few comments/suggestions on this manuscript as detailed below: The title is too long and can be abbreviated.1.
Review of hematological malignancies presenting as priapism i.e. including CLL and Acute leukemia would benefit the readers in developing insight on the conditions in which priapism could be the presenting feature.

2.
The meaning of some of the sentences is not clear in several places.The authors may focus on improving the language of the paper.Reviewer Expertise: Hemato-Oncology, Genomics, Single-cell sequencing, Flow cytometry I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above.

Wulyo Rajabto
Division of Hematology-Medical Oncology, Department of Internal Medicine, Dr. Cipto Mangunkusumo General Hospital, Faculty of Medicine, University of Indonesia, Jakarta, Indonesia This case report emphasizes the importance of priapism as the rare clinical presentation of chronic myeloid leukemia so that as a clinician we should think if there is patient with priapism the secondary causal is chronic myeloid leukemia.The treatment of priapism consists of: 1) Local factor by urologist who performs intra cavernous aspiration 2) The systemic factor by hematologist who administers leucapheresis (mechanical and drug eg.Hydroxyurea) and TKIs such as Imatinib.
I find the title of this manuscript indeed captivating.Besides describing the priapismus phenomenon in CML, the author also showed to us a comparison study among several previously published cases known worldwide, that I think it is a very interesting plus point.
Title: I believe it is very interesting, straightforwardly describes the case.

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Introduction: I believe it contains concise reasoning why the author brought up this case, ○ emphasizes the rare of similar cases, and interestingly presents one of CML emergencies.
Case presentation: The author successfully managed to present the case elaborately along with valid data.
○ Discussion: The author describes the case comprehensively, referred to similar case studies before, from the clinical course to the outcome, as mention on table 1. Reviewer Expertise: CML, lymphoma, anemia I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.
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Figure 2 .
Figure 2. Treatment and outcome from priapism and CML.

3 . References 1 .
James Johnson M, Hallerstrom M, Alnajjar HM, Frederick Johnson T, et al.: Which patients with ischaemic priapism require further investigation for malignancy?.Int J Impot Res.2020; 32 (2): 195-200 PubMed Abstract | Publisher Full Text 2. Ali EA, Sardar S, Yassin MA: Priapism in lymphoproliferative disorders: A systematic review.Hematol Oncol Stem Cell Ther.2021.PubMed Abstract | Publisher Full Text 3. Gogia A, Sharma A, Raina V, Gupta R: Priapism as an initial presentation of chronic lymphocytic leukemia.Leuk Lymphoma.2012; 53 (8): 1638-9 PubMed Abstract | Publisher Full TextIs the background of the case's history and progression described in sufficient detail?YesAre enough details provided of any physical examination and diagnostic tests, treatment given and outcomes?YesIs sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment?PartlyIs the case presented with sufficient detail to be useful for other practitioners?YesCompeting Interests: No competing interests were disclosed.

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Is the background of the case's history and progression described in sufficient detail?YesAre enough details provided of any physical examination and diagnostic tests, treatment given and outcomes?YesIs sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment?YesIs the case presented with sufficient detail to be useful for other practitioners?YesCompeting Interests: No competing interests were disclosed.

Table 1 .
Case report review from last than twenty years.