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Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of chronic myeloid leukemia (CML), granting patients a life expectancy close to that of the normal population and, in a subset of patients, the possibility to discontinue therapy. Nonetheless, for a not negligible minority of patients, TKIs are not able to control CML. Allogeneic hematopoietic cell transplantation (HCT) has long been a pivotal therapy for CML. At present, allogeneic HCT is considered an option in CML patients diagnosed or progressing to blast phase (BP), for those in chronic phase (CP) resistant to multiple lines of TKI therapy or for those experiencing severe toxicity, mostly hematologic, under TKIs.
- chronic myeloid leukemia
- allogeneic stem cell transplantation
- TKIs
1. Indication for HCT and TKIs Treatment as “Bridge to Transplant”
Herein, we presented three patients who performed HCT from unrelated donors between 2013 and 2018. These cases exemplified actual indications for HCT, which remains an important option for the minority of patients who still progress to ABP and for CML patients resistant or intolerant to two or more TKIs [5,6,7].
CML AP occurs in a minority of patients at diagnosis (overall incidence 3.5% [8]), with worse outcomes compared to patients diagnosed in CP as, despite the improvement attained with TKIs, lasting remissions are often lacking [9]. Eligibility for HCT in this subset of patients has not changed much over the last 10 years. In 2013, when our clinical case #1 occurred, eligibility criteria for HCT included losing a response previously achieved with TKIs or persistence of molecular disease after second-line therap [10]. At present, both ELN 2020 recommendations and the latest NCCN guidelines suggest that a patient diagnosed in AP should be treated with a TKI (generally a second generation one) followed by evaluation of HCT if the response is not optimal, while a disease progressing from CP to AP during TKIs therapy should be immediately considered for HCT [11,12]. Outcomes of HCT in AP CML are generally inferior to those performed in CP [13,14], although Jiang et al. demonstrated an advantage in OS for HCT over TKI in AP-CML patients [15] in a prospective study. Our patient matched the favorable prognostic factors for OS in ABP CML undergoing allogeneic HCT reported in an EBMT study by Radujkovic et al., i.e., a controlled disease at transplant, young age (<45 years), good performance status and a short time from diagnosis to transplant and an HLA-matched donor [16]. These characteristics could explain the favorable outcome of the few short-term complications; the lack of long-term complications; and the long-lasting, deep molecular response, even without maintenance treatment.
Clinical cases #2 and #3 exemplify the role that HCT still holds in the management of CML patients in first CP failing 2G or 3G TKIs or experiencing severe hematologic toxicity to one or multiple TKIs, which frequently leads to a suboptimal response due to inability to treat patients with effective doses and/or duration of TKIs [17].
Case #2 showed the appearance of clonal chromosomal aberrations (CCA) other than loss of Y chromosome in the Ph-negative clone, which has been associated with reduced survival in CP CML patients treated with various TKIs [18]. Indeed, in some cases, Ph-negative clones with additional CCA are associated with myelodysplastic syndrome/acute myeloid leukemia, mainly in patients with chromosome 7 abnormalities but also in patients with isolated trisomy 8. These cases should be monitored very carefully and may become eligible for other treatments [6] and for quick referral to transplantation. Both cases raise the question about the impact of prior TKI therapy on HCT feasibility and post-transplant complications. In fact, both patients received two lines of TKI treatment (nilotinib and imatinib in case #2, nilotinib and ponatinib in case #3) before HCT. A prospective study performed by EBMT demonstrated the feasibility of HCT in patients previously treated with 2G-TKIs (dasatinib, nilotinib and bosutinib) with engraftment and a post-transplant immunological complications rates comparable to that of TKI-naïve or imatinib-treated patients [19]. In another large series of patients, the favorable outcome seems to be due to a deepening of molecular response before HCT under newer TKIs, without an increase in non-relapse mortality (NRM) [20]. Thus, while 2G-TKIs seem to have no impact on the outcome after transplant, little is known about the effect of prior use of the 3G-TKI ponatinib. A retrospective study performed by Chaladon et al. [21] described 44 patients treated with ponatinib and HCT, showing no differences in OS, progression-free survival (PFS), relapse incidence or NRM when compared to other TKIs. In conclusion, the patients’ histories and the available clinical studies confirm that the administration of TKIs favorably impacts subsequent HCT [21,22], independently from the TKI generation and from the number of lines.
Asciminib, a first-in-class allosteric inhibitor of BCR-ABL1 kinase activity, has now been approved by FDA and EMA for the treatment of patients who failed two lines of therapy or in patients with T315I mutation, and it may represent a strategy that our clinical cases could not benefit from and a possible alternative to HCT. In the ASCEMBL study [22], asciminib demonstrated superior efficacy vs. bosutinib and an improved safety profile with a low rate of treatment discontinuation (5.8% vs. 21.1%, respectively). However, as described by Yeung et al. [23], the relevant comparator of asciminib is ponatinib, and a randomized trial will be needed to clarify the optimal treatment pathway. Considering the current data, asciminib represents the optimal strategy in patients with intolerance to previous TKI therapy, and it could have been a great therapeutic option for clinical case #2.
2. The Transplant Procedure
Optimal conditioning intensity for HCT in the TKIs era is crucial. A large retrospective study performed by Chhabra et al. [24] evaluated 1395 CML patients aged between 18 and 60 years who underwent HCT. Of them, myeloablative (MAC) and reduced intensity conditioning regimen (RIC) were performed in 1204 and 191 patients, respectively. Multivariable analysis showed no significant difference in OS between MAC and RIC groups. In addition, leukemia-free survival and NRM did not differ significantly between the two groups. Compared with MAC, the RIC group had a higher risk of early relapse after HCT (hazard ratio (HR), 1.85; p = 0.001). The cumulative incidence of chronic GVHD was lower with RIC than with MAC (HR, 0.77; p = 0.02). Clinical cases #1 and #2 were transplanted around the age of forty years after MAC regimens, with a follow-up after transplantation free from complications. The third patient, who received the transplant at 63 years, experienced chronic GVHD and other immunological complications such as immune-mediated neutropenia and severe AIHA requiring repeated and prolonged steroid treatment. Even if conditioning at reduced toxicity has allowed for performing HCT, it is a matter of fact that chronic GVHD and the prolonged immunosuppression required by GVHD can cause significant morbidity, especially in elderly patients. New strategies for GVHD prevention and treatment, such as post-transplant cyclophosphamide and JAK2 inhibitors, may reduce the burden of mortality and morbidity linked to GVHD also in elderly patients in the near future.
3. Follow-up after Transplantation: TKIs Treatment and Donor Lymphocytes Infusions (DLI)
One important issue linked to the follow-up after transplantation is the use of TKIs as a maintenance or pre-emptive strategy. Larger analyses of TKI maintenance tried to assess the effectiveness of this approach in setting Philadelphia chromosome-positive leukemias. In acute lymphoblastic leukemia (ALL), two retrospective studies from the EBMT Acute Leukemia Working Party [20] and MD Anderso [25], respectively, suggest that the use of TKIs after transplant is associated with improved outcomes and is recommended in Ph+ ALL.
In CML, TKIs or/and DLI can be administered after HCT as pre-emptive treatment in patients transplanted in APB or driven by minimal residual disease (MRD) recurrence in patients in the first CP at transplant. No recommendations or prospective studies were reported, and all the available data come from retrospective analyses, with larger experience with imatinib [26] compared to 2G- or 3G-TKIs. As expected, responses were deeper and more prolonged in molecular relapses, and no clear advantage between TKIs and DLI could be detected [27]. A recent study from the Center for International Blood and Marrow Transplant Research tried to answer whether the administration of TKIs after HCT is associated with improved outcomes for patients with CML [28]. A total of 390 adult patients who underwent transplantation between 2007 and 2014 and received maintenance TKI following HCT (n = 89) compared with no TKI maintenance (n = 301) were analyzed. All patients had received TKI therapy before HCT. The majority of patients had a disease status of first CP at HCT (n = 240; 62%). After a median follow-up of 61 months (range: 7–97 months) in the maintenance TKI group and of 68 months (range: 2–98 months) in the no maintenance group, the adjusted estimates for 5-year relapse (maintenance 35% versus no maintenance 26%; p = 0.11), leukemia-free survival (maintenance 42% versus no maintenance 44%; p = 0.65) or OS (maintenance 61% versus no maintenance 57%; p = 0.61) did not differ significantly between the two groups.
The strategy adopted by most transplant centers, including our team [29], is to use the TKI that was best tolerated and that had achieved the deepest response before HCT and to strictly monitor molecular MRD: if MRD negativity/undetectable disease is obtained, TKI therapy is continued until progression or adverse effects; in the case of disease persistence, DLIs can be associated and/or switch to a different TKI may be considered.
This entry is adapted from the peer-reviewed paper 10.3390/hemato4030020
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