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Comprehensive management of a 24-year-old patient with B-cell acute lymphoblastic leukemia post-bone marrow transplant and severe graft-versus-host disease- A case report
*Corresponding author: Kumar Saket, Department of Maxillofacial Surgery, Rajiv Gandhi University of Health Sciences, Bengaluru, Karnataka, India. saket0410@gmail.com
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Received: ,
Accepted: ,
How to cite this article: Saket K, Radhakrishnan VS. Comprehensive management of a 24-year-old patient with B-cell acute lymphoblastic leukemia post-bone marrow transplant and severe graft-versus-host disease-A case report. J Cutan Aesthet Surg. doi: 10.25259/JCAS_114_2024
Abstract
A 24-year-old patient with B-cell acute lymphoblastic leukemia underwent high-dose chemotherapy followed by allogeneic bone marrow transplantation (BMT) according to the BMT 2000 protocol. The post-transplant course was complicated by the development of severe, Grade 4 graft-versus-host disease (GVHD), with multiorgan involvement and significant facial disfigurement. This condition not only posed life-threatening challenges but also led to profound psychological and social consequences. Management required a comprehensive, multidisciplinary approach combining long-term immunosuppressive therapy to control immune activity, advanced cosmetic surgical interventions to restore facial form, and supportive care aimed at preserving organ function. Over the course of 5 years, the patient gradually stabilized and reached an asymptomatic state with ongoing immunosuppressive therapy, showing no acute adverse effects. This case emphasizes the complexity of treating advanced GVHD following BMT and highlights the importance of integrating immunologic, cosmetic, and supportive strategies. Sustained multidisciplinary care and long-term follow-up are critical to improving both survival and quality of life in such patients.
Keywords
Avascular necrosis
B-cell acute lymphoblastic leukemia
Bone marrow transplant
Cosmetic intervention
Graft-versus-host disease
Immunosuppressive therapy
Multiorgan graft-versus-host disease
INTRODUCTION
The malignant hematologic condition known as B-cell acute lymphoblastic leukemia (ALL) is typified by the proliferation of immature lymphoblasts in the bone marrow and peripheral blood. It is among the most prevalent malignancies in children and young adults. By restoring normal hematopoiesis and reconstituting the immune system, traditional treatment methods, including chemotherapy and allogeneic bone marrow transplantation (BMT), can considerably improve survival rates and perhaps lead to long-term remission. It also entails significant hazards, most notably the possibility of developing graft-versus-host disease (GVHD), which is a leading cause of morbidity and death among recipients of transplants. Following allogeneic stem cell transplantation (hematopoietic stem cell transplantation), GVHD is still a frequent consequence. 5–30% of cases still show treatment resistance despite advancements in pretransplant conditioning, preventative measures, and graft manipulation.1 In GVHD, the skin is usually the first and most often damaged organ.
Mid-to-high-potency topical steroids are frequently effective in treating localized acute cutaneous GVHD and chronic cutaneous GVHD, which mostly affects the epidermis. However, switching to other topical treatments or systemic options is typically necessary when prolonged treatment is required.2 Pimecrolimus 3 and tacrolimus4,5 are two other topical therapies. Thirteen of the eighteen patients with persistent cutaneous GVHD responded well to tacrolimus 0.1% ointment in a study by Choi and Nghiem,5 albeit more treatments were eventually needed to control the skin condition.
Facial deformity due to GVHD causes major psychological and social issues, in addition to the physical burden of the disease. To address these cosmetic sequelae, advanced cosmetic interventions are essential, including dermatologic therapies and reconstructive surgery. However, there is a dearth of research on all-encompassing, long-term therapeutic approaches that include both systemic and cosmetic rehabilitation. This case report provides a thorough description of a young girl who had severe cosmetic and multiorgan problems as a result of Grade 4 GVHD following BMT. It highlights how crucial an integrated treatment plan is to achieving consistent long-term results and improving quality of life through functional recovery and cosmetic rehabilitation.
CASE REPORT
A 24-year-old man received a diagnosis of B-cell ALL and was treated using the BMT 2000 protocol. This protocol, which combines high-dose chemotherapy and allogeneic BMT, is frequently utilized in high-risk ALL patients. A myeloablative conditioning regimen is usually part of this protocol, which is intended to eradicate leukemic cells and facilitate the engraftment of donor hematopoietic stem cells.
Overview of the BMT 2000 protocol
For 2 days, cyclophosphamide (60 mg/kg/day) was given to suppress the immune system and eliminate any remaining leukemic cells. Given in divided doses over 3–4 days, total body radiation with a dose range of 12–14 Gy is used to eradicate any residual cancer cells and prepare bone marrow for transplantation. Methotrexate (10–15 mg/m2) is given after transplantation to stop GVHD by preventing T-cell proliferation.
Initiation of cyclosporine (3–5 mg/kg/day) is done to keep immunosuppression going and avoid GVHD. The patient experienced severe Grade 4 GVHD, a potentially fatal complication caused by the donor’s immune cells attacking the host tissues, despite the rigorous conditioning program.
Cosmetic and mucosal complications
Disfigurement of the face and hyperpigmentation
The patient experienced severe face discoloration and scarring. He had pico laser therapy, which uses pulses lasting 450 picoseconds with a wavelength of 755 nm to reduce hyperpigmentation. Six sessions, spaced every 4 weeks, made up the treatment. Every 2–3 weeks, chemical peels (20–35% glycolic acid, 20% salicylic acid) were applied to enhance the skin’s texture and support the laser treatment. The overall tone was improved for 6 months using two sessions of cosmelan peel [Figure 1].
- Progressive depigmentation response following combined laser and chemical peel therapy.
Lip hyperpigmentation
The Neodymium-doped Yttrium Aluminum Garnet laser (ND: YAG) laser, which targets excessive melanin production in the skin at a wavelength of 311 nm, was used to treat the patient’s hyperpigmented lips. Melanin in the hyperpigmented tissues is specifically broken down by this excimer laser, leaving the surrounding tissue unaffected. Eight to ten sessions were scheduled, 1 week apart, for the treatment. The pigmented areas were gradually lightened by applying concentrated bursts of laser light during each 15– 20 min session. After 3–4 sessions, a noticeable improvement was anticipated, and by the end of the treatment cycle, full results were anticipated. The patient was also instructed to use a depigmenting cream with chemicals such as kojic acid or hydroquinone twice a day to maximize the results. It was also stressed to regularly use sunscreen with an SPF of 30 or higher to stop future ultraviolet (UV)-induced pigmentation. The goal of this method was to restore the natural tone of the lips while lessening the appearance of hyperpigmentation [Figure 2].
- Results of Neodymium-doped Yttrium Aluminum Garnet laser (ND: YAG) laser treatment on hyperpigmented lips, showing progressive lightening after eight to ten sessions, with ongoing depigmenting cream application.
Dipigmented limbs
In addition, the patient had depigmentation in the limbs, which was addressed with tacrolimus ointment and excimer laser therapy. A 308 nm excimer laser was utilized, which is well-known for its effectiveness in treating depigmentation and localized vitiligo. The targeted application of the laser to the afflicted areas took place twice a week over the 15 sessions that made up the therapy program. Six to eight weeks after treatment, improvements in pigmentation were expected, with a progressive return of color in the treated areas. The patient also used twice a day tacrolimus 0.1% ointment on the areas that were depigmented. Tacrolimus is an immunomodulator that helps to restore pigmentation by stimulating melanocytes to promote repigmentation and lowering inflammation. Follow-up appointments were planned regularly to track skin reaction and modify the treatment plan as necessary. This comprehensive strategy was designed to supplement the patient’s entire treatment plan by addressing the psychological and cosmetic effects of depigmentation [Figure 3].
- (a) Before and (b) after images of depigmented limbs treated with excimer laser therapy and tacrolimus ointment, highlighting repigmentation progress over 15 sessions.
Hair loss and thinning
Treatment for severe hair loss caused by scalp GVHD included growth factor concentrates (GFC), platelet-rich plasma (PRP) therapy, and supportive dietary supplements. Each 4–6 weeks, 3–4 mL of the patient’s own PRP is injected into the scalp as part of PRP therapy. Because PRP contains a high concentration of growth factors, this therapy seeks to promote hair growth and improve the repair of hair follicles. In addition, GFCs were given topically to enhance scalp health and promote follicle healing. The patient was prescribed oral doses of zinc (50 mg/day) and biotin (5,000 mcg/day), both of which are known to boost hair health and strength, to assist hair regrowth [Figure 4].
- Scalp appearance pre- and post-platelet-rich plasma therapy, showing hair regrowth and improved follicle health after multiple treatment cycles.
Restoring eyebrows after GVHD alopecia
The patient’s post-GVHD consequences included extensive eyebrow baldness. The patient’s eyebrows were transplanted, with 200–250 hair follicles inserted per eyebrow to restore natural density. To promote long-term hair retention and stop additional follicular shrinking, the patient was also prescribed 1 mg of finasteride per day for 3 years after the transplant [Figure 5]. Microblading was used to modify the shape and create a more defined, visually pleasant appearance, which improved the transplanting process even more. In addition to treating the alopecia, this integrated strategy attempted to raise the patient’s self-esteem and general quality of life [Figure 6].
- Eyebrow restoration post-graft-versus-host disease alopecia, illustrating successful hair follicle transplantation with enhanced density and microblading for improved aesthetics.
- Overall quality of eyebrow improvement following comprehensive cosmetic and therapeutic interventions and microblading for graft-versus-host disease effects.
GVHD in the mouth with mucosal involvement
Along with severe oral mucositis and oral GVHD, the patient also experienced erythema and painful ulcers. A common symptom of persistent GVHD is oral GVHD, which frequently results in ulcers, irritation, and dryness on the mucosal linings.
Mucositis management
Enchantment for pain relief and mucosal protection, mouthwash containing 2% lidocaine, 12.5 mg/5 mL diphenhydramine, and aluminum hydroxide/magnesium hydroxide was advised to be used 4–6 times a day. To lessen inflammation of the oral mucosa, topical corticosteroids were used twice a day, such as clobetasol gel (0.05%). In severe situations, patients were provided systemic analgesics such as morphine (5–10 mg every 4–6 h as needed) to treat their discomfort.
Manage GVHD orally
Two times a day, mouthwash containing tacrolimus (0.1 mg/mL) was used to reduce local immunological responses in the oral mucosa. The systemic features of oral GVHD were managed with the continuing use of systemic immunosuppressants, such as prednisone (1 mg/kg/day), mycophenolate mofetil (MMF) (1–1.5 g twice daily), and cyclosporine (3–5 mg/kg/day). To treat dry mouth (xerostomia), artificial saliva and pilocarpine (5 mg 3 times daily) were administered.
Multiorgan GVHD and systemic treatment: Liver GVHD: Aggressive immunosuppression and frequent monitoring of liver function tests were necessary due to liver damage. Based on the response, prednisone (1–2 mg/kg/day) was reduced. The T-cell-mediated immunological response was suppressed with the aid of MMF (1.5 g twice daily). A daily dose of 3–5 mg/kg of cyclosporine kept serum trough levels between 200 and 400 ng/mL stable. For GVHD that was resistant to steroids, ruxolitinib (10 mg twice a day) was introduced.
Ocular GVHD
The patient’s ocular GVHD caused dry eyes. Preservative-free artificial tears were used 4–6 times a day to treat him; in more severe cases, topical cyclosporine (0.05%) was given twice a day to protect the ocular surfaces and minimize inflammation.
Prolonged immunosuppressive treatment
The patient was kept on long-term immunosuppressive treatment, with prednisone (at first 1 mg/kg/day) tapered off over 2 years according to the patient’s clinical response. For 2 years, MMF (1 g twice daily) was administered; after the patient stabilized, the dosage was tapered. To avoid toxicity, cyclosporine (3 mg/kg/day) was maintained with routine blood level monitoring.
Avascular necrosis and orthopedic intervention
Bilateral avascular necrosis of the femoral heads occurred in the patient 2 years after BMT; this condition was probably brought on by long-term corticosteroid use. Bilateral complete hip replacements restored his mobility. Following surgery, physiotherapy was started, and bisphosphonates (alendronate 70 mg once weekly) were administered to limit additional bone loss [Figure 7].
- Bilateral femoral neck necrosis treated with total hip replacement as shown in X-ray (arrows).
Outcome and follow-up
The patient is asymptomatic and has not displayed any signs of an ALL or GVHD relapse 5 years following the BMT. He continues regular follow-up visits every 6 months to assess liver function, oral health, and joint stability. The patient now enjoys a much higher quality of life, no history of recurrence, and has no persistent systemic or cosmetic problems.
DISCUSSION
This case study describes the difficult care of a male patient, 24, who had an allogeneic BMT for B-cell ALL and developed severe Grade 4 GVHD. The treatment plan used here emphasizes the importance of a multidisciplinary approach, especially when dealing with the systemic, mucosal, and cosmetic aspects of GVHD.
GVHD management
Treatment indications
Because Grade 4 GVHD has a substantial impact on the patient’s quality of life and has the potential to be fatal, it requires intensive therapy. Patients with gastrointestinal or mucosal symptoms, hepatic failure, and severe skin involvement usually need supportive treatment in addition to systemic immunosuppressive therapy.
Treatment protocols
First-line treatment
Topical therapies in conjunction with modifying systemic calcineurin inhibitor (CNI) levels should be the mainstay of care for patients with grade I acute GVHD.6 Oral antihistamines and moisturizers might also be necessary to reduce skin irritation and shield it from harm.6,7
Second-line therapy
Depending on side effects and availability, there is no better second-line treatment. In patients with steroid-refractory cutaneous GVHD, extracorporeal photopheresis (ECP) achieves 82% complete responses and is well tolerated, avoiding widespread immunosuppression.8,9 In children, MMF elicits a 79% complete response.10 Tumor necrosis factor antagonists work well for gastrointestinal involvement, and in steroid-refractory instances, daclizumab shows 58% full responses.11 With improved skin reactions, anti-thymocyte globulin aids in the depletion of T-lymphocytes.12 UVA-1 phototherapy is helpful for isolated cutaneous GVHD; full responses have been documented in 70% of cases.10 In addition, narrowband UVB is promising.13
Treatment for chronic GVHD
Topical treatments are usually the first choice for mild cases of chronic GVHD, particularly when a graft-versus-leukemia (GVL) effect is required.14 If the disease involves organs such as the liver or fascia, systemic steroids could be required, which worsens the result, especially in situations of thrombocytopenia or acute GVHD development.8,14 For cutaneous chronic GVHD, several skin-directed treatments can be used as adjuncts to speed up the tapering of systemic immunosuppression or as monotherapy.14-22
Moisturizers containing urea and glycerol improve moisture, while lubricants help soothe irritation and stop breakdown in intact skin.16 Topical steroids continue to be the mainstay of treatment for modest skin involvement despite the paucity of evidence supporting their use; mid-to-high potency alternatives are advised for the body, while lower-potency options are advised for sensitive areas.22 When higher steroids are not acceptable, topical CNIs can be helpful; tacrolimus ointment has been demonstrated to be beneficial in 72% of patients.23 Phototherapy is beneficial for patients with severe skin involvement when combined with UVA-1 and MMF.20
High-potency steroids are commonly used in the oral mucosa, with clobetasol showing superior efficacy over dexamethasone.24 Phototherapy has also demonstrated efficacy for oral lesions, and topical tacrolimus provides advantages that save the steroid.18,25
Treatment for chronic GVHD
Skin-directed therapy: Topical treatments are given priority for mild chronic GVHD, particularly when a GVL effect is sought.14 When topical medications cannot treat organ involvement (liver, fascia, etc.), systemic steroids are taken into consideration. This is especially true when there is thrombocytopenia or acute GVHD development, which can have a detrimental effect on outcomes.8,14 Numerous skin-directed therapies are available, either as stand-alone interventions or as supplements to systemic medications, enhancing local responses and facilitating a more rapid reduction in immunosuppression.14-22
Systemic intervention
First-line therapy for moderate-to-severe chronic GVHD usually entails taking 1 mg/kg/day of prednisone, maybe in addition to a CNI.14 Two weeks later, the dosage is progressively reduced. Alternative treatment plans, such as rituximab and MMF, have demonstrated encouraging response rates, even if corticosteroids are still the primary treatment option.26 With reported response rates of 60–80%, ECP is a promising second-line treatment for mucocutaneous chronic GVHD.27 In a considerable number of patients, MMF has also been successful in relieving symptoms.28,29
Tyrosine kinases are the target of imatinib mesylate, which has been used to treat steroid-refractory sclerotic GVHD and shown notable improvements.30 In addition, favorable effects have been demonstrated by rituximab, especially in steroid-refractory cases.31,32 Other choices are low-dose methotrexate, which has shown a 90% response rate in combination therapy,33 and rapamycin, which has a 65% response rate in cutaneous involvement.34
Cutting-edge therapy
Novel medications, such as ibrutinib, which maximizes GVL benefits while reducing GVHD, are being investigated.31,35,36 GVHD symptoms may be lessened by Janus kinase inhibitors such as tofacitinib and ruxolitinib.32-35 Clinical investigations have demonstrated decreased incidence rates of GVHD, suggesting a potential role for histone deacetylase inhibitors in its prevention.36
CONCLUSION
The complicated and frequently crippling side effect of BMT known as severe GVHD calls for an all-encompassing, multidisciplinary approach to therapy. This example highlights the importance of tailored supportive treatment in addition to aggressive systemic immunosuppression to effectively manage the major quality-of-life concerns and systemic manifestations of GVHD. The positive long-term result this patient had emphasizes the need for continued research into novel treatments as well as the possibility for better management techniques. There is hope for improved treatment procedures that can alleviate symptoms and boost outcomes for patients coping with this difficult condition as our understanding of GVHD advances. To improve care and maximize outcomes, patients, researchers, and healthcare professionals must continue to collaborate.
Authors’ contributions:
All authors have contributed equally in designing the review article, writing, and revising. All authors contributed to the article and approved the submitted version.
Ethical approval:
Institutional Review Board approval is not required.
Declaration of patient consent:
The authors certify that they have obtained all appropriate patient consent.
Conflicts of interest:
There are no conflicts of interest.
Use of artificial intelligence (AI)-assisted technology for manuscript preparation:
The authors confirm that there was no use of artificial intelligence (AI)-assisted technology for assisting in the writing or editing of the manuscript, and no images were manipulated using AI.
Financial support and sponsorship: Nil.
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