Clinical Features, Cancer Biology, Transplant Approach and Other Integrated Management Strategies for Wiskott–Aldrich Syndrome

Figures & data

Figure 1 Treatment decision algorithm for WAS/ XLT based on the severity of clinical symptoms, type of genetic mutation, and WASp expression. For patients with classic WAS with a suitable MSD/MUD donor or CB 5-6/6 or 4/6 with a good cell dose, an early transplant should be performed. In the absence of a suitable matched donor, a Haploidentical transplant or gene therapy trial should be discussed. XLT patients with severe thrombocytopenia or mutation suggestive of a severe phenotype and absent WASp expression should also be transplanted.

Table 1 Supportive Care in WAS

Thrombocytopenia
General measures	Avoid contact sports, NSAIDs, and aspirin
Major bleeding	Platelet transfusions
	Indicated only for active clinical bleeding/pre-procedural Use only irradiated, CMV-negative, and leuco-reduced products Minimize prophylactic platelet transfusions due to the risk of alloimmunization
Minor bleeding	Antifibrinolytic agents
Mucocutaneous bleeding	Aminocaproic acid: 100 mg/kg loading dose, followed by 50–100 mg/kg every 6 hrs × 7–10 days
Menorrhagia	Tranexamic acid 1300 mg every 8 hrs for 5 days at the start of menstruation
ITP Suspect when no appropriate increment in platelets or resolution of clinical bleeding after platelet transfusion	IVIG 1 mg/kg single dose or steroids (first line) Rituximab 375 mg/m^2 weekly for 4 weeks (second line)
Refractory thrombocytopenia	Splenectomy Normalizes platelet count and mean platelet volume, but associated high risk of post-splenectomy sepsis especially post-transplant
Other Investigational agents for thrombocytopenia	Eltrombopag and IL-2 being studied in clinical trials
Recurrent Infections
Immunoglobulin replacement	400–600 µg/kg should be started for all classical WAS and XLT with infections IV every 3 weekly or SQ weekly Higher doses of IgG replacements needed in WAS compared to other IEIs due to higher catabolism
Prophylactic antimicrobials
Antibacterial and PJP prophylaxis	Trimethoprim/Sulfamethoxazole 30 mg/kg once daily (based on trimethoprim component)
Recurrent respiratory tract infections/ Pneumonia	Azithromycin (For immunomodulatory action) 10 mg/kg PO × 3 days/week
Antiviral and antifungal	Routine prophylaxis not indicated Acyclovir considered in case of recurrent herpes simplex virus infections Antifungals are considered for patients with a history of fungal infections
Vaccines	All live viral vaccines are contraindicated due to risk of infection from the vaccine strain Do not administer any vaccines other than flu vaccine once immunoglobulin replacement is started
Eczema
General measures	Skin hydration using emollients and moisturizers is the key Dietary modification including hypoallergenic formula
Topical steroids	Use thick creams/ointments with low/no water content Desonide 0.05%, hydrocortisone 2.5% (low potency) Fluocinolone 0.025%, triamcinolone 0.1%, betamethasone dipropionate 0.05% (medium to high potency)
Severe recalcitrant eczema	Dermatology consultation, wet wraps, dupilumab (IL-4 receptor alpha antagonist)
Pruritus associated with eczema	Oral antihistamines

Table 2 Allogenic HSCT in WAS and Their Salient Features

Author	Study Details				Salient Features
	No. of Patients	Study Period	Conditioning	Survival
Filipovic et al 2001^Citation57	170	1968–1996	Non TBI	OS (5 yrs): 70% MSD: 87% MUD: 71% MMFD: 52%	● Excellent survival for MSD transplant ● MUD transplants in patients <5 years had survival close to MSD HSCT ● MMRD and MUD transplants >5 years has worse outcomes
Ozsahin et al 2008^Citation50	96	1979–2001	Bu/Cy	OS MSD 88% URD 71% MMRD 55% EFS (7 yrs): 75%	● Post-transplant autoimmunity is strongly associated with mixed/split chimerism (due to residual host lymphocytes) ● Splenectomy increased the risk of infectious complications
Kobayashi et al 2006^Citation58	57	1985–2004	Bu/Cy, Bu/Cy/ATG Radiation-containing regimen	OS (5 yrs): 73% MUD: 80% CB: 80% FFS: 65.7%	● Non-busulfan conditioning regimen noted to be associated with poor outcome factor on multivariate analysis
Pai et al 2006^Citation59	23	1990–2005	Bu/Cy, Bu/Cy/ATG	OS: 78.2% MUD 77% MMRD (only 2 patients) 0%	● Loss of donor chimerism detected first in myeloid conversion ➔ loss of donor platelets reconstitution followed by donor B-cell chimerism
Moratto et al 2011^Citation51	194	1980–2009	Bu/Cy: MAC Melphalan/ Treosulfan + Fludarabine: RIC	OS (5 yrs):84% Transplants beyond the year 2000 OS 89.1%	● Improved outcomes for MMRD and MUD > 5 years of age ● Incomplete lymphocyte reconstitution, post-transplant autoimmunity high with mixed chimerism ● Donor myeloid chimerism <50% resulted in persistent thrombocytopenia
Shin et al 2012^Citation22	47	1990–2009	Bu/Cy/ATG Other MAC/RIC	OS (5 yrs): 92%	● OS significantly better after 2000 when compared to before 2000 (90.8% vs 62.5%)
Shekhovtsva et al 2017^Citation60	90	1996–2013	MAC: Bu/Cy, Bu/Flu, Bu/Cy+ orhers, Treo/Flu Cy/Hydroxyurea RIC: Bu/Cy Flu/Mel ± Treo	Only UBC OS (5 yrs): 75% EFS (5 yrs): 70%	● Superior EFS demonstrated for age <2 yrs at the time of transplant and XLT patients
Elfeky et al 2018^Citation61	34	1996–2016	Bu/Cy/Alem Treo/Flu/Alem Flu/ Mel/Alem	OS: 100%	● Myeloid chimerism correlates with post-transplant platelet counts
Balashov et al 2018^Citation62	32	2012–2017	Treo/Flu/Mel/ATG + G-CSF & Plerixafor	OS: 91%	● No survival difference between Haploidentical vs MUD transplants (93.8% vs 88.5%) ● 100% full donor chimerism ● Addition of G-CSF & Plerixafor to the conditioning along with TCR αβ+/CD19+ cell depletion improved graft success
Burroughs et al 2020^Citation4	129	2005–2015	MAC: Bu/Cy or Mel Bu/Flu RIC: (Bu AUC <50 mg × h/l) Bu/Cy Bu/Flu	OS (5 yrs): 91%	● Age <5 yrs superior OS (94% vs 66%) ● Intensity of conditioning regimen, affected T-cell and myeloid engraftment but not survival ● RIC (specifically Flu/Mel): achieved < 50% donor myeloid chimerism

Abbreviations: TBI, total body irradiation; MSD, matched sibling donor; MUD, matched unrelated donor; MMFD, mismatched family donor; URD, unrelated donor; MAC, myeloablative conditioning; RIC, reduced intensity conditioning; Bu, busulfan; Cy, cyclophosphamide; ATG, anti-thymocyte globulin; Flu, fludarabine; Mel, melphalan; Treo, treosulfan; Alem, alemtuzumab; G-CSF, granulocyte colony stimulating factor; AUC, area under the curve; OS, overall survival; EFS, event-free survival.

Table 3 HSCT Vs Gene Therapy

Previous Experience	“Proven Curative Therapy” (50 Years of Experience)	Offered Only as “Clinical Trial” (10 Years of Experience)
Conditioning regimen	MAC: MAC preferred over RIC (Due to low risk of mixed donor chimerism) Nonmyeloablative: Used only in patients in whom MAC usage is restricted due to organ dysfunction	RIC: Busulfan + Fludarabine
Viral vector	N/A	Retroviral vector showed good engraftment and WAS protein reconstitution but high risk for leukemogenesis (7/10 patients). w1.6W LV vector used in 34 patients (no clonal selection reported with some patients with almost a decade of follow-up)
Correction of underlying abnormalities	Corrects all abnormalities provided full donor chimerism results Correction of thrombocytopenia needs at least >50% myeloid donor chimerism.	Substantial improvement of all listed abnormalities without full expression of WASp in all hematopoietic cell lines. Thrombocytopenia increased from pretreatment values with an improvement of MPV, improved frequency and severity of bleeding episodes.
WASp expression	Selective advantage for T cells≫ B cells≫ Myeloid cells	Variable levels of reconstitution (lymphocyte selective advantage)
Complications	Acute and long-term toxicity from the conditioning regimen like Acute and chronic GVHD Mixed donor chimerism Post-transplant autoimmunity Malignancy post HSCT	No severe side effects related to gene therapy were reported with lentivirus (LV). However, the risk of insertional oncogenesis/clonal expansion exists. None reported so far. The longest follow-up is 8.8 years, still long-term data are needed.
Age	<5 years and preferably <2 years good outcomes	Can be performed even in older patients/adults who are considered high risk for HSCT.
Ongoing research		A cryopreserved product is being used to increase safety (Currently being tested in a clinical trial: NCT03837483)
Future scope		Improvement in vector construct to increase transgene expression Evaluate the use of cryopreserved formulation of w1.6W-transduced autologous CD34+ HSPC. Refinement of conditioning regimen to increase gene-corrected myeloid engraftment^Citation80

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