Allogeneic Hematopoietic Cell Transplantation for Chronic Lymphocytic Leukemia

Background and Aim: In the recent years, the treatment options of chroniclymphocytic leukemia (CLL) have literally been revolutionized with theinvention and use of pathway inhibitors (PWIs), including ibrutinib,idelalisib, and venetoclax. These treatment modalities have alteredthe standard treatment of CLL, which have also challenged the role ofallogeneic hematopoietic cell transplantation (allo-HCT). Nevertheless,the optimum dose, duration, long-term efficacy and toxicity as well as ofthese agents, are not yet fully defined. A significant proportion of patientsdiscontinue their treatment over time because of intolerance. Moreover,the disease is either refractory or progresses after a short period of time ina proportion of patients. Thus, in such cases, the prognosis of the diseasemight be dismal while allo-HCT could represent the treatment of choice.The allo-HSCT modality can impose a long-term control of disease withcurative potential in the case of CLL, particularly with reduced-intensityconditioning (RIC) and overcomes the poor prognostic impact of 17pandfludarabine-refractoriness. In this study, the current applications ofallo-HCT as a treatment option for the CLL is presented.Results: In the case of CLL, the disease might be considered as the highriskissue if one/more of the following conditions are met: (i) diseaserefractory to purine analogues; (ii) disease relapsing within 2 years afterthe chemoimmunotherapy (CIT); and (iii) disease with deletion and/ormutation of the TP53 gene. The CIT-resistant patients outlooks seem to bemarkedly improved by the use of PWIs. In fact, the current findings supportthe notion of a combined approach with PWI and allo-HCT, which canbe used either before the transplantation to reduce tumor burden, or after the transplantation to treat the relapse of the disease. Altogether, severalstudies on the RIC allo-HCT in CLL have highlighted the progression-freesurvival (PFS) and overall survival (OS) rates of 50%-60% and 60%-75%,respectively, at 2 years. At 5 years, the rates were 35%-45% and 45%-65%, respectively. After allo-HCT, the long-term follow-up studies report10-year PFS of approximately 30%. In a large registry study conductedby the European Society for Blood and Marrow Transplantation (EBMT) aswell as in the prospective CLL3X trial, the PFS rate at 10 years post-allo-HCT was about 79% for the patients who passed the 5-/ 6-year landmarkevent-free. Approximately, 30% of all transplanted patients might durablybenefit from a targeted GVL effect, while the TP53 abnormalities havenot been associated with an inferior outcome after RIC-allo-HCT inmost of the studies. A refractory disease at allo-HCT seems to be themost important risk factor for an adverse transplant outlook. As a result,patients, who have been transplanted in remission might have a betteroutcome with PFS rates of 55%-65% at 2 years. In addition to diseaserelatedrisk factors, the patient- and procedure-related variables (e.g., sexmismatch, age, donor type, T cell depletion and performance status) andthe center experience might determine the outcome of the allo-HCT. Theearly-death rate of CLL allotransplants appeared to be less than 5% bymeans of the modern transplantation approaches. The good tolerabilityof RIC-allo-HCT might allow application of the procedure in older casesand patients with comorbidity. However, the non-relapse mortality(NRM) may increase to over 40% at 2 years post-transplant in patientswith adverse patient-, donor- and procedure-related risk factors, in largepart because of the graft versus host disease (GvHD)-related problems.Nevertheless, in patients with a combination of favorable risk factors atallo-HCT, the 2-year risk of NRM reduces to 12%. Apart from its impacton NRM, chronic GvHD is the major determinant affecting the qualityof life after allo-HCT. About 25% of survivors will experience impairedquality of life during the first post-transplant years because of chronicGVHD. A recent study by the EBMT has confirmed the significant impactof using ibrutinib as a bridge to transplant strategy indicated the principleof association between PWI and allo-HCT. Besides, in the untransplantedpatients, the prognosis of CLL relapse post-transplant seemed not tobe inferior to that of high-risk CLL. The advent of PWIs (e.g., ibrutinib)has considerably improved the treatment options of the high-risk CLLprogressing after the allo-HCT. Accordingly, some recent data proposethat the safety and efficacy of ibrutinib given for CLL relapse afterallotransplant are as good as in the untransplanted patients. Furthermore,Th1-mediated GVL effects may be enhanced by ibrutinib if given on adonor chimerism scenario. Accordingly, the outcome of post-transplantrelapse in CLL patients has significantly improved. Open issues of allo-HCT in the PWI era are largely related to the interactions of PWI andtransplantation. Some emerging evidence has accentuated that PWI cansafely bridge the CIT-refractory patients to transplant. In addition, theuse of PWI for the prevention of early disease recurrence post-transplantwarrants thorough studies.Conclusion: In comparison with what can be achieved using othertreatment approaches, the use of an allogeneic SCT in CLL must weighup both the risks of the morbidity of the transplant and its outcome.As the currently available novel agents become increasingly used incombination and earlier in the disease course, the allo-HCT might bebeneficial for patients who fail or are intolerant or even do not haveaccess to these novel agents. Taken all, the optimal timing of the allo-HCT continues to be of the focus of some ongoing clinical investigations,which seems to be the basis of randomized prospective clinical trials.

کلیدواژه ها:

Allogeneic hematopoietic cell transplantation ، Chronic lymphocytic leukemia