Abstract
Purpose of Review
Cellular therapy using T cells modified to express chimeric antigen receptors (CAR-T cells) has had striking success in patients that have failed previous treatment for CD19+ B cell non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia (CLL), or acute lymphoblastic leukemia (ALL). Curative therapy for this group of diseases has previously been limited to allogeneic hematopoietic cell transplantation HCT (alloHCT). The recent results of CAR-T cell therapy raise the question of how best to integrate CAR-T cell therapy and alloHCT in the care of these patients.
Recent Findings
Within the past 2 years, results from larger trials and increased follow-up of patients treated with CD19 CAR-T cell therapy suggest that some may achieve durable remission without transplant.
Summary
The balance of efficacy and toxicity for CAR-T cell therapy and alloHCT vary by disease type, disease status at the time of treatment, patient characteristics, and the specific therapy employed. There are early signals that subsequent transplantation of patients who have achieved remission with CAR-T may be a potentially viable (though expensive) strategy.
We’re sorry, something doesn't seem to be working properly.
Please try refreshing the page. If that doesn't work, please contact support so we can address the problem.
Introduction
Prior to 2010, allogeneic hematopoietic cell transplant (alloHCT) was the only curative treatment for patients with high-grade lymphoma relapsed after autologous HCT (autoHCT), relapsed acute lymphoblastic leukemia (ALL), and advanced chronic lymphocytic leukemia (CLL). Dramatic reports of the success of chimeric antigen receptor (CAR) T cell therapy in treating patients with relapsed or refractory disease [1, 2] and the duration of some remissions have raised the possibility that some responding patients may be cured. Six studies presented in the past 2 years, the Phase II expansion cohort of ZUMA-1 [3], the JULIET trial [4•], the TRANSCEND trials of JCAR014 [5••] and JCAR017 [6••], and trials from the University of Pennsylvania [7•] and Memorial Sloan Kettering Cancer Center (MSKCC) [8••] provide the first measures of long-term efficacy of CAR-T cells in the treatment of aggressive B cell lymphoma (principally DLBCL) and ALL.
These data contributed to the recent FDA approvals for CAR-T cell therapy in the treatment of children and young adults with relapsed/refractory ALL and adults with relapsed/refractory DLBCL. In addition to the FDA-approved indications, the availability of clinical trials led to the consideration of CAR-T cell therapy in patients with B cell malignancies that are either multiply relapsed, refractory to chemo- or immunotherapy, or that have relapsed following alloHCT. The data also create clinical scenarios where both CAR-T therapy and alloHCT could be considered. CAR-T therapy is an attractive option to reduce or eliminate residual disease prior to alloHCT, because CAR-T therapy has low treatment-related mortality, and because studies of patients with low- or high-grade follicular lymphoma (FL) [9], ALL [10,11,12], Hodgkin’s disease (HD) [13] or DLBCL [14] have consistently shown that transplants performed in the presence of active disease have inferior outcomes and higher rates of relapse.
In this review, we begin by addressing whether prior therapies, including alloHCT, impact the safety or efficacy of CAR-T cell therapy. Next, for specific hematologic diseases, we review evidence that guide two critical decisions: first, whether to offer CAR-T therapy to patients with residual disease or to proceed directly with alloHCT, and second, given the knowledge that pre-transplant preparative regimens will likely wipe out CAR-T cells, whether to consolidate remissions obtained via CAR-T cell therapy though the use of alloHCT or to delay transplantation until there is evidence of progressive disease. Finally, we review some general factors to consider with regard to initiating transplant or CAR-T cell therapies in patients who are potential transplant candidates.
Impact of Prior Therapy on CAR-T Cell Therapy Safety and Efficacy
The use of CAR-T cell therapy requires in vitro expansion of lymphocytes transduced with a gene encoding the CAR protein and infusion of the cell product into patients [15, 16, 17•]. Among patients previously treated with alloHCT, these lymphocytes are derived from the donated stem cell graft. Donor lymphocyte infusion is an effective practice for patients who relapse after alloHCT and have low donor chimerim, but is followed by the development of graft versus host disease (GVHD) in approximately 45% of treated patients [11]. Infusion of allogeneic lymphocytes modified with a CAR could also result in GVHD. Surprisingly, in three separate studies of patients with ALL [8••, 18, 19] and an additional study of patients with CLL and B cell lymphoma [20] who had relapsed following alloHCT, none developed GVHD when subsequently treated with CAR-T cells despite the allogeneic origin of the cells. The reason for this difference is not understood. Nonetheless, clinical experience shows that the major toxicities of CAR-T cell therapy, including the cytokine release syndrome and neurotoxicity, are not apparently increased by prior allogeneic transplantation [19, 21].
Review of recent key clinical trials of CAR-T cells (summarized in Table 1) support the hypothesis that there is little, if any, influence of the number of prior lines of chemotherapy or prior use of the bi-specific T cell engager (BiTE), blinatumomab [29], on the success of CAR-T cell therapy. Two potential mechanisms may result in therapeutic resistance: patients may develop immunity to the protein sequence within the CAR binding domain and reject cells expressing CAR protein [19, 33] or the shared epitopes may exert strong selective pressure favoring the emergence of antigen-negative tumor variants [34••]. In the case of ALL, initial findings reported complete remissions (CRs) following treatment with CAR-T cells in two of three patients that had experienced relapses after blinatumomab [18], suggesting that relapse following this CD19-directed antibody therapy does not preclude success of CD19-directed CAR-T cell therapy (though in one of the two patients, the remission lasted only 2 months). These data suggest that neither the number of failed prior lines of chemotherapy nor prior treatment with alloHCT have strong impacts on the outcome of patients treated with CAR-T cell therapy.
Specific Disease Considerations
Acute Lymphoblastic Leukemia
A complete remission is achieved in approximately 90% of adults with ALL following initial induction chemotherapy [35]. European and American expert panels recommend that allogeneic transplantation for adults with ALL be restricted to those in first remission with high-risk disease, those that fail to achieve a first remission, or those that suffer a subsequent relapse [36, 37]. The definition of high-risk adult ALL continues to evolve, but generally includes patients who present with a high white blood cell count, who harbor the Philadelphia chromosome (Ph + disease) or with Ph-like ALL [38]. Patients harboring mutations or translocation involving the mixed lineage leukemia (MLL) gene, including the t (4;11), may also be a high-risk group [39]. The persistence of minimal residual disease (MRD), defined as leukemia cells present below the frequency detectable by morphology [40], at the time of allografting, predicts inferior transplant outcomes: in one study, patients who underwent alloHCT in the absence of MRD had a 3-year overall survival of 68% compared to only 40% for those transplanted at a time when MRD was detectable [11]. Thus, if HCT is being considered for patients with high-risk ALL in CR1, methods to obtain an MRD-negative CR may improve outcomes [41].
If the decision is made to withhold HCT until after an initial relapse, a challenge then is to get patients back into second remission, since HCT outcomes are superior for patients in CR2 compared to those with refractory relapse. Studies of conventional chemotherapeutic approaches to adult patients with relapsed or recurrent ALL showed CR rates of 20 to 44% [42•, 43•] and median overall survival of 24 weeks [44]. However, several newer therapies, including blinatumomab and inotuzumab ozogamacin [45], have recently completed phase III trials showing impressive rates of response in relapsed or refractory ALL. In a phase three trial of 326 patients randomized 2:1 to either inotuzumab ozogamacin or standard chemotherapy, the CR rate was 80.7% with inotuzumab ozogamacin versus 29.4% with standard chemotherapy [28]. In addition, 78.4% of patients with a complete remission were found to be MRD negative [28] and 41% of patients proceeded to HCT. A similarly designed trial found that blinatumomab resulted in a CR or CR with incomplete count recovery in 44% of patients of whom 76% were MRD negative [29]. Despite these results, the median overall survival of patients treated with blinatumomab was 7.7 months, reinforcing the need for subsequent therapy.
CD19-directed CAR-T cells offer another, perhaps more effective approach for patients with relapsed/recurrent or refractory ALL. A phase I/II trial from MSKCC enrolled 53 adults with ALL [8••] obtained CR in 83%, including 67% that were free of MRD. Among 9 patients in whom residual disease remained detectable, all relapsed; while among 32 patients without MRD, 16 patients relapsed. In this cohort, 26 patients achieved a complete remission following CAR-T cell infusion and were followed without further treatment. Nine of these patients remain alive at a median of 29 months of follow-up. Among 17 patients who proceeded to HCT, 5 remain alive, 6 relapsed, and 6 died from transplant-related toxicities. Comparing outcomes of the 32 patients that achieved an MRD-negative CR following CAR-T cell infusion, no difference in overall survival was seen between patients who completed HCT and those that did not.
A phase I trial at the University of Pennsylvania treated 30 young adults and children with relapsed/refractory ALL with CAR-T cells and found a CR rate of 90% and a 6-month event-free survival rate of 67% [7]. As noted above, half of these patients had previously completed an alloHCT. Among 30 patients treated with a defined composition of CD4+ and CD8+ CAR-T cells at FHCRC [19], all patients achieved a complete remission when evaluated by bone marrow morphology, and 29 had no evidence of disease by high-resolution flow cytometry. At the time of publication, 12 of 17 patients (70%) treated with fludarabine plus cyclophosphamide lymphodepletion prior to CAR-T cell infusion remained alive and free of relapse, and 10 completed alloHCT. Overall, the rate of alloHCT following CAR-T cell therapy compares favorably to the 24% rate following treatment with blinatumomab [29].
CAR-T cell persistence is one key difference between trials that may impact clinical decision-making. The trial at MSKCC, which provides the longest follow-up of ALL patients treated with CAR-T cells, found no difference between event-free or overall survival between patients in whom the CAR-T cells persisted for more than or less than 14 days [8••]. However, cross-trial comparisons find shorter persistence of T cells (median 14 days) and higher rates of relapse or death among patients who achieved an MRD-negative CR (17 of 26, 58%) among patients reported by Park et al., as compared to patients who achieved an MRD-negative CR following treatment with tisagenlecleucel where the median duration of CAR-T persistence was 168 days and the risk of death or relapse by 1 year was only 41% [7•]. The reason for this difference is not known, but differences in the age of trial participants, manufacturing process, and CAR design, including the costimulatory domains used may be factors. Nevertheless, the observation that some of the patients reported by Park et al. achieved durable complete remissions in the absence of CAR-T cell persistence suggests that ongoing antileukemic activity of CAR-T cells may not be required for durable remissions [8••, 46].
Taken together, the available data on CAR-T cells show that they are highly active in adults with recurrent or chemo-resistant ALL, result in a complete remission in most patients, and that a subset of these remissions persist with no further therapy. Thus, there are likely to be several key roles of CAR-T cell therapy for ALL. One is to obtain remissions for patients in first relapse who are refractory or not eligible for other therapies in order to induce a remission prior to allogeneic transplantation. These patients may consider alloHCT as consolidation following successful remission with CAR-T cell therapy. A second possible role is to obtain an MRD-negative first remission in patients who have suboptimal responses to initial chemotherapy. An additional role is for treatment following relapse after alloHCT has failed. Among this population, a second myeloablative transplant is associated with increased toxicity and low success rates [47], but newer preparative regimens may allow this approach to be feasible [48]. A central question is whether it will be possible to distinguish those CAR-T cell-induced CRs that will persist without further therapy from those that are likely to be short lived. If such a distinction was possible, the toxicities of alloHCT could be avoided in patients who may not require the additional therapy.
High-grade B Cell Lymphoma
Patients with DLBCL who relapse within 1 year after autoHCT or who are refractory to initial therapy have a dismal prognosis. This is well documented in the retrospective SCHOLAR-1 trial [23••] in which 861 refractory or relapsed patients had a 26% objective response and a 7% complete response to their next line of therapy. Use of newer agents (venetoclax or ibrutinib) does not significantly improve on this result [49, 50]. The combination of lenalidomide plus ibrutinib achieved an objective response rate of 44% and a complete response of 14% in a small group of patients [51], but grade 3/4 adverse events occurred in 89% of patients treated and the duration of response has not been reported. Addition of ofatumumab to traditional salvage regimens such as DHAP resulted in a CR rate of 15%, and only 33% of patients completed a subsequent autoHCT [52]. These results provide a useful benchmark against which CAR-T cell therapy for DLBCL can be compared.
Given the dismal prognosis of non-transplant approaches to recurrent DLBCL, a number of investigators have explored the use of alloHCT following ablative or reduced intensity conditioning regimens [14, 27••, 53, 54]. Similar to ALL, transplants performed for DLBCL in the presence of active disease have inferior outcomes and higher rates of relapse. In the GITMO study of large cell lymphoma [14], pre-transplant disease status was the only variable to remain a significant predictor of outcomes in multivariate analysis (with 1-year overall survival being approximately 80%, 60%, and 50% for patients transplanted in complete remission, partial remission, and with chemorefractory disease respectively). Thus, patients most likely to benefit from alloHCT are those with few, if any, comorbidities, and with disease that is in either partial or complete remission.
Three recent key trials of CD19-directed CAR-T products have shown efficacy in diffuse large B cell lymphoma: ZUMA-1 [3•, 22], JULIET [4•, 24•], and TRANSCEND [26•]. The ZUMA-1 trial was larger (n = 111 patients), and 64% of the enrolled patients with DLBCL had ≥ 3 prior lines of chemotherapy, 30% with primary refractory disease [3•]. All three trials showed impressive results in this difficult to treat population with manageable toxicity. The JULIET trial is notable for lower CR rates and longer time to infusion, but also allowed the use of bridging chemotherapy. The rate of CR reported from TRANSCEND was 58% among patients treated at dose level 2 (108 CAR-T cells), the highest of the three trials. Interestingly, no relationship between the number of prior lines of therapy and response was seen.
A key finding is that PR does not appear to be a meaningful endpoint in this setting: patients that failed to attain a complete response had a median progression-free survival of only 1.9 months after treatment with axicaptagene ciloleucel [3•] and 2.1 months after treatment with lisocabtagene maraleucel [26•]. In contrast, patients who remain alive and in complete remission 12 months after CAR-T cell therapy appear to be at very low risk of relapse. In the case of axicaptagene ciloleucel, the number of relapses after 12 months was zero [3•]. Taken together, these data suggest that CAR-T therapy is qualitatively distinct from chemotherapy: with the expectation that roughly 50% of the patients with DLBCL treated with CAR-T will experience a complete remission, and of these, approximately 60% will not show progression within the subsequent 12 months and might be cured. Of the 101 patients enrolled in ZUMA-1, only two subsequently completed alloHCT.
When would one consider alloHCT for DLBCL? Cross-trial comparisons show similar 1-year survival rates among patients with chemorefractory DLBCL treated with RIC alloHCT or CAR-T cell therapy; however, non-relapse mortality (NRM) of CAR-T cell therapy is approximately 3% while NRM associated with alloHCT is ~ 30%. Thus, the above data provide a strong argument that CAR-T cell therapy supplants alloHCT for patients with chemorefractory DLBCL. In addition, low relapse rates after the first 12 months suggest that a substantial fraction of patients with DLBCL treated with CAR-T cells may be cured. Extrapolating from the GITMO study, one may hypothesize that outcomes could be optimized by targeting alloHCT to patients with responses that are unlikely to prove durable, i.e., patients treated with CAR-T cells who achieved no response or a partial response or patients that achieve a subsequent remission via conventional chemotherapy.
The impact of CAR-T therapy on the outcomes of subsequent transplant is unknown. Thus, to integrate the science of CAR-T cell therapy with transplantation, researchers must identify patients at high risk of relapse following CAR-T. These high-risk patients may have a window of opportunity for good outcomes if offered a RIC alloHCT during CR. In an unselected population of patients treated with CAR-T cell therapy for DLBCL, the toxicity of a subsequent RIC alloHCT for patients in CR would likely outweigh any benefit.
Indolent Non-Hodgkin Lymphoma and CLL
Grades one and two follicular lymphoma (FL), mantel cell lymphoma (MCL), and small/chronic lymphocytic lymphoma (SLL/CLL) represent indolent lymphomas that are frequently responsive to chemotherapy but are unlikely to be cured in the absence of transplantation. AlloHCT is an effective but infrequently used treatment strategy for FL, MCL, and CLL because other options have become available. For example, the 5-year survival after relapse of FL treated with salvage combination chemotherapy and autologous stem cell transplantation is nearly 70% [55]; the expected 10-year overall survival is 66% [56]. Early progression is a poor prognostic factor correlated with historic 5-year overall survival measures near 50%, but recent improvements such as the incorporation of immunomodulatory medications, such as thalidomide and lenalidomide [57, 58], and targeted agents [59,60,61] have improved the outlook of these patients. Mantle cell lymphoma represents a particularly challenging disease, but newer agents have shown some promise [62, 63].
Recently, a registry analysis from CIBMTR of patients with FL found that RIC alloHCT resulted in a 5-year progression-free survival of 58% and 5-year overall survival of 66% [27••], while patients who completed an autoHCT had a 5-year progression-free survival of 41%. In a landmark analysis of patients surviving >24 months, the authors report that beyond 2 years after transplant, the early toxicity of alloHCT becomes offset by lower relapse rates translates into an overall survival benefit of alloHCT. Similarly, long-term outcomes reported from the German CLL study group describe 10-year overall survival following alloHCT for high-risk or refractory CLL of 51% [32].
CAR-T cell therapy is not yet approved by the FDA for treatment of indolent lymphomas. Because these tumors tend to be responsive to multiple therapies, short remissions alone provide limited value. Improved long-term outcomes, such as matching the 5-year survival of 66% seen from the CIBMTR, are a reasonable benchmark. Small trials of CAR-T cell therapy for CLL are encouraging; however, the results with low-grade lymphoma are mixed. Patients with ibrutinib refractory CLL treated with CAR-T cells at FHCRC had a CR rate of 71% at 4 weeks, with 58% having no malignant IGH sequences identified on deep sequencing. The absence of malignant IGH sequences was associated with progression-free survival of 100% at a median follow-up of 6.6 months [30]. Treatment of other indolent lymphomas with CAR-T cells was reported to result in a CR in 2 of 9 patients [6••]. Thus, CLL appears to be particularly responsive to CAR-T cells. Follicular lymphoma can follow either an indolent or an aggressive course. Among the 23 patients with follicular lymphoma treated with CTL019, the complete response rate was 71% and at a median follow-up of 28.6 months, 70% of patients remained progression free [24•]. Monitoring a subset of 16 patients with quantitative polymerase chain reaction for CAR-T cell persistence revealed that 8 had loss of CAR-T cells without an associated relapse. This finding, along with the plateau of the progression-free survival curve, suggests that, similar to the case with DLBCL and CLL, a subset of patients with aggressive follicular lymphoma may be cured by CAR-T cell therapy. Thus, while the option to engage in CAR-T cell therapy for indolent lymphomas and CLL is likely to be dictated by the availability of clinical trials, referral for such a therapy should be considered at the time of relapse following autoHCT or when progression following ibrutinib therapy is seen. This strategy would leave several targeted options (i.e., idelalisib, copanlisib [64], and venetoclax [31, 65]) in addition to salvage chemotherapy available for reinduction therapy enabling a possible subsequent alloHCT should the patient relapse after CAR-T cell therapy.
Multple Myeloma
Myeloma shares key features with CD19+ target malignancies: a target antigen, B cell maturation antigen (BCMA), has been identified that is highly expressed and mostly limited to the malignant cell population. As a result, “on target, off tumor” toxicity was expected to be limited, and indeed updated results from recent trials of the bb2121 CAR product showed no instances of dose-limiting toxicity or grade ≥ 3 neurotoxicity. BCMA targeted CAR-T cells showed modest success in early results of multiply refractory patients, with 2 of 6 patients achieving a CR or VGPR [66•]. Increasing the CAR-T cell dose to ≥ 150 × 106 cells significantly improved outcomes with ORR rates of 95% in 22 patients [67•, 68•]. Responses appear deep: 50% of patients obtained a CR, and 90% of these were negative for MRD. The rate of progression-free survival at 9 months was 71%. Importantly, the high cell dose remains associated with a tolerable safety profile. Consideration of BCMA CAR-T cell trials will depend on local availability and will likely be restricted to patients with relapsed/refractory disease. While the above results were limited to patients with high BCMA expression, future trials may expand eligibility, as even low levels of BCMA can trigger CAR-T cells in vitro [69•]. Follow-up data are limited; there is no data regarding transplant following treatment with BCMA CAR-T cells.
Acute Myeloid Leukemia
The challenges of myeloid leukemia set this disease target apart from B cell and plasma malignancies because no single clearly optimal target antigen has been defined. Very few antigens present on leukemic blasts are absent from normal maturing hematopoetic stem cells [70••]. As a result, CAR-T cells targeted at antigens present on HSCs cells may result in marrow aplasia. Though trials testing CAR-T cells targeting CD33, CD123, mesothelin, Muc1, CD56, CD38, or CD117 individually and in combination are in progress [71], specific challenges exist in engineering CAR-T cells to respond to combinations of target antigens [72]. So-called logic gated CAR-T cells, which require the presence of two or more antigens, may overcome this limitation by gaining specificity. Early responses of myeloid leukemia to CD33 CAR-T cells have been brief, lasting ~ 12 weeks [73].
Transplant Following CAR-T Cell Therapy: the Importance of CAR-T Cell Persistence
A key feature of cellular immunotherapy is persistence of the transferred cells. In early studies of CAR-T cells for chronic lymphocytic leukemia, those with early cell proliferation and sustained CAR-T cell numbers achieved a complete remission [74], whereas relapses occurred exclusively among patients with loss of the transfused cells. In patients with ALL, Maude et al. [7•] reported that following infusion, CAR-T cells were detectable for a median of 168 days, along with the expected associated B cell aplasia. Approximately 50% of relapsing patients developed loss of CD19 on their tumor. This supports the hypothesis that ongoing antitumor activity of CAR-T cells likely contributes to the maintenance of remissions in treated patients, and points to the general observation that two major routes of relapse are loss of CAR-T cells or loss of their target antigen on the tumor, i.e., CD19-negative relapse. While follow-up was brief, among 17 patients treated with fludarabine and cyclophosphamide conditioning, the only patient to relapse with CD19+ disease had completed an alloHCT. The duration of CAR-T cell persistence necessary for a long-term remission in the absence of subsequent alloHCT is unknown and may vary depending on disease type. These data also illustrate that alloHCT following CAR-T therapy risks effectively trades potentially persistent CAR-T cells that may be responsible for the ongoing maintenance of a remission for a non-specific graft-versus-leukemia effect.
Pace of Disease and Other Considerations
An important detail regarding interpretation of the results of trials of CD19-directed CAR-T therapy lies in the implicit selection criteria imposed by the manufacture of a modified cell therapy product. CAR-T cell therapy requires apheresis of the patient’s blood, isolation of circulating T cells, gene transfer, usually with a viral vector, and subsequent expansion in the cell-processing facility prior to infusion back into the patient [5••]. The manufacture times for these products are typically between 2 and 3 weeks. Lymphodepletion prior to modified CAR-T cell infusion is usually delayed until the modified cell product is cleared for clinical use. As a result, patients with rapidly progressing disease may not be able to wait to begin treatment. Reviewing the high rates of production success and infusion without the need for patients to withdraw from trials to receive urgent chemotherapy may suggest that these trials enrolled patients who were both medically fit and could wait several weeks to initiate therapy. This trial design may bias against patients with aggressive disease and improve apparent outcomes relative to a cohort enrolled at presentation (rather than at treatment).
In the future, “intent to treat” trial designs that allow bridging chemotherapy may reduce bias. In addition, improved technologies such as virus-free techniques that rely on DNA transposases are likely to speed manufacture [75, 76] and the use of gene-editing techniques to disrupt the endogenous T cell receptor [77] or the use of engineered NK cells [78] may provide a “universal” product available “off the shelf” to patients regardless of matched histocompatability. These innovations will likely broaden the types of patients who benefit from CAR-T cell therapy.
Recent data suggest that outcomes following use of alternative donor stem cell sources, specifically haploidentical family members [79] and banked cord blood (CB) units [80], are similar to those following transplant with matched unrelated donors. These results have made allogeneic stem cell grafts available for nearly all patients, and therefore donor availability seldom enters into the decision to initially pursue a CAR-T cell approach versus an allogeneic transplant. In the case of the DLBCL, matched related donors were compared to unrelated donors matched at 8 of 8 major histocompatibility loci and no impact of donor type (sibling donor versus matched unrelated) was found on overall survival [53]; similar recent results for patients with ALL were also reported [81]. The Italian group found Hodgkin disease patients with an available allogeneic donor had improved survival in comparison to those patients for whom an allogeneic donor was not available [13]. However, this cohort did not list patients with available suitable CB units, and only 13% of the patients in the “donor available” group received a haploidentical HCT.
It is unlikely that patients’ other pretreatment characteristics will identify alloHCT or CAR-T cell therapy as a preferred treatment. None of the recent CAR-T cell trials has shown an association between prior treatment (either prior autoHCT, prior alloHCT, or the number of prior chemotherapy regimens) and outcome. While patient selection for alloHCT has been increasingly refined through the use of predictive algorithms that can define the likelihood of non-relapse mortality within the first 2 years after transplant [82], such algorithms do not yet exist for CAR-T cell therapy, making comparisons between predictive risk scores impossible. Baseline pretreatment factors identified by Sorror et al. [82] predict non-relapse mortality associated with both myeloablative and non-myeloablative alloHCT. These factors can stratify patient groups with probabilities of 2-year overall survival as high as 71% or as low as 34%. However, patients identified as high risk for alloHCT may not have other attractive treatment options, so transplantation, though high risk, may still offer the best chance of both short and long-term survival. Indeed, criteria identifying patients as high risk for alloHCT (principally the presence of organ dysfunction) were also exclusion criteria for several pivotal trials of CAR-T cell therapy [3•, 4•, 6••, 22].
Differences in the characters of risk across the two treatment types may influence patient decision-making. Whereas the principle toxicity risk of CAR-T cell therapy is acute [83, 84], the long-term morbidity associated with GVHD [85, 86] is a unique feature of alloHCT. Thus, it remains challenging to quantitatively compare the risks of alloHCT and CAR-T therapy for individual patients.
Conclusions
The rapid growth of new treatment options for diseases with historically dismal prognoses [23••, 62, 87] is both exciting and challenging. As these data are new, significant uncertainty remains. The choice to offer HSCT to patients following CAR-T cell therapy relies on historical experience that transplantation has been the only curative option for the subset of patients with relapsed aggressive B cell malignancies. As experience with CAR-T cell therapy grows and long-term remissions prove durable, the use of transplantation may be further refined.
References
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
•• Grupp SA, Kalos M, Barrett D, Aplenc R, Porter DL, Rheingold SR, et al. Chimeric antigen receptor–modified T cells for acute lymphoid leukemia. N Engl J Med. 2013;368(16):1509–18 Case reports describing the first two patients to receive meaningful doses of CAR-T cells for hematologic malignancy.
Kochenderfer JN, Wilson WH, Janik JE, Dudley ME, Stetler-Stevenson M, Feldman SA, et al. Eradication of B-lineage cells and regression of lymphoma in a patient treated with autologous T cells genetically engineered to recognize CD19. Blood. 2010 Nov 18;116(20):4099–102.
• Neelapu SS, Locke FL, Bartlett NL, Lekakis LJ, Miklos DB, Jacobson CA, et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med. 2017;377(26):2531–44 Phase 2 trial treating 111 patients with 2 × 10 6 CAR-T (ZUMA-1).
• Schuster SJ, Bishop M, Tam C, Waller EK, Borchmann P. Primary analysis of Juliet: a global, pivotal, phase 2 trial of CTL019 in adult patients with relapsed or refractory diffuse large B-cell lymphoma. In: ASH Abstract [Internet]. 2017 [cited 2018 Mar 21]. p. 577. Available from: https://ash.confex.com/ash/2017/webprogram/Paper105399.html. Initial report of the phase 2 trial treating 99 patients with tisengenlecleucel for r/r DLBCL.
•• Sommermeyer D, Hudecek M, Kosasih PL, Gogishvili T, Maloney DG, Turtle CJ, et al. Chimeric antigen receptor-modified T cells derived from defined CD8+ and CD4+ subsets confer superior antitumor reactivity in vivo. Leukemia. 2016;30(2):492–500 Study provides rationale and data to support the cooperativity of CD4 and CD8 cells in therapeutic efficacy.
•• Turtle CJ, Hanafi L-A, Berger C, Hudecek M, Pender B, Robinson E, et al. Immunotherapy of non-Hodgkin’s lymphoma with a defined ratio of CD8+ and CD4+ CD19-specific chimeric antigen receptor–modified T cells. Sci Transl Med. 2016;8(355):355ra116–6 Careful analysis of patients treated with CAR-T identified pitfalls of CAR-T cell therapy, including the development of immune responses to CAR proteins, predictors of cytokine release syndrome, dynamics of CAR-T expansion, and the importance of fludarabine in lymphodepletion.
• Maude SL, Laetsch TW, Buechner J, Rives S, Boyer M, Bittencourt H, et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Engl J Med. 2018;378(5):439–48 Phase 2 trial of tisegenlecleucel for children and young adults with ALL.
•• Park JH, Rivière I, Gonen M, Wang X, Sénéchal B, Curran KJ, et al. Long-term follow-up of CD19 CAR therapy in acute lymphoblastic leukemia. N Engl J Med. 2018;378(5):449–59 Long-term follow-up provides insight into the outcomes of patients who achieve remission by CAR-T cell therapy and the importance of differences in T cell persistence between various CAR-T cell products.
Kuruvilla J. The role of autologous and allogeneic stem cell transplantation in the management of indolent B-cell lymphoma. Blood. 2016;127(17):2093–100.
Zhou Y, Slack R, Jorgensen JL, Wang SA, Rondon G, Lima M de, et al. The effect of peritransplant minimal residual disease in adults with acute lymphoblastic leukemia undergoing allogeneic hematopoietic stem cell transplantation. Clin Lymphoma Myeloma Leuk. 2014;14(4):319–326.
Bar M, Wood BL, Radich JP, Doney KC, Woolfrey AE, Delaney C, et al. Impact of minimal residual disease, detected by flow cytometry, on outcome of myeloablative hematopoietic cell transplantation for acute lymphoblastic leukemia. Leuk Res Treat. 2014;2014:1–9.
Zhang M, Fu H, Lai X, Tan Y, Zheng W, Shi J, et al. Minimal residual disease at first achievement of complete remission predicts outcome in adult patients with Philadelphia chromosome-negative acute lymphoblastic leukemia. PLOS ONE. 2016;11(10):e0163599.
Sarina B, Castagna L, Farina L, Patriarca F, Benedetti F, Carella AM, et al. Allogeneic transplantation improves the overall and progression-free survival of Hodgkin lymphoma patients relapsing after autologous transplantation: a retrospective study based on the time of HLA typing and donor availability. Blood. 2010;115(18):3671–7.
Rigacci L, Puccini B, Dodero A, Iacopino P, Castagna L, Bramanti S, et al. Allogeneic hematopoietic stem cell transplantation in patients with diffuse large B cell lymphoma relapsed after autologous stem cell transplantation: a GITMO study. Ann Hematol. 2012;91(6):931–9.
Gill S, Maus MV, Porter DL. Chimeric antigen receptor T cell therapy: 25 years in the making. Blood Rev. 2016;30(3):157–67.
June CH, Sadelain M. Chimeric antigen receptor therapy. N Engl J Med. 2018;379(1):64–73.
• Till BG, Jensen MC, Wang J, Chen EY, Wood BL, Greisman HA, et al. Adoptive immunotherapy for indolent non-Hodgkin lymphoma and mantle cell lymphoma using genetically modified autologous CD20-specific T cells. Blood. 2008;112(6):2261–71 First study to demonstrate safety of CAR-T cells in humans.
Maude SL, Frey N, Shaw PA, Aplenc R, Barrett DM, Bunin NJ, et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med. 2014;371(16):1507–1517.
Turtle CJ, Hanafi L-A, Berger C, Gooley TA, Cherian S, Hudecek M, et al. CD19 CAR–T cells of defined CD4+:CD8+ composition in adult B cell ALL patients. J Clin Invest. 2016;126(6):2123–38.
Brudno JN, Somerville RPT, Shi V, Rose JJ, Halverson DC, Fowler DH, et al. Allogeneic T cells that express an anti-CD19 chimeric antigen receptor induce remissions of B-cell malignancies that progress after allogeneic hematopoietic stem-cell transplantation without causing graft-versus-host disease. J Clin Oncol. 2016;34(10):1112–21.
Ghosh A, Smith M, James SE, Davila ML, Velardi E, Argyropoulos KV, et al. Donor CD19 CAR T cells exert potent graft-versus-lymphoma activity with diminished graft-versus-host activity. Nat Med. 2017;23(2):242–9.
Locke FL, Neelapu SS, Bartlett NL, Siddiqi T, Chavez JC, Hosing CM, et al. Phase 1 results of ZUMA-1: a multicenter study of KTE-C19 anti-CD19 CAR T cell therapy in refractory aggressive lymphoma. Mol Ther. 2017;25(1):285–95.
•• Crump M, Neelapu SS, Farooq U, Neste EVD, Kuruvilla J, Westin J, et al. Outcomes in refractory diffuse large B-cell lymphoma: results from the international SCHOLAR-1 study. Blood. 2017;130(16):1800–8 Retrospective analysis illustrating the poor prognosis of patients with r/r DLBCL and justifying the use of CAR-T cell therapy.
• Schuster SJ, Svoboda J, Chong EA, Nasta SD, Mato AR, Anak Ö, et al. Chimeric antigen receptor T cells in refractory B-cell lymphomas. N Engl J Med. 2017;377(26):2545–54 Results of 28 patients treated with r/r DLBCL or follicular lymphoma showing high response rates.
Nagle SJ, Kaitlin W, Schuster Stephen J, Nasta Sunita D, Edward S, Rosemarie M, et al. Outcomes of patients with relapsed/refractory diffuse large B-cell lymphoma with progression of lymphoma after autologous stem cell transplantation in the rituximab era. Am J Hematol. 2013;88(10):890–4.
• Abramson JS, Palomba ML, Gordon LI, Lunning MA, Arnason JE, Wang M, et al. High durable CR rates in relapsed/refractory (R/R) aggressive B-NHL treated with the CD19-directed CAR T cell product JCAR017 (TRANSCEND NHL 001): defined composition allows for dose-finding and definition of pivotal cohort. Blood. 2017;130(Suppl 1):581–1 Phase 2 study of 74 patients treated with JCAR017 for aggressive lymphoma. Double- and triple-hit patients had an ORR of 81%. Defined composition of the CAR product revealed a therapeutic window of improved safety.
•• Klyuchnikov E, Bacher U, Kröger NM, Hari PN, Ahn KW, Carreras J, et al. Reduced-intensity allografting as first transplantation approach in relapsed/refractory grades one and two follicular lymphoma provides improved outcomes in long-term survivors. Biol Blood Marrow Transplant. 2015;21(12):2091–9 In considering transplant of low-grade lymphomas, this paper illustrates the differences in short- and long-term outcomes with auto- versus alloHCT. In addition, it provides a comparison point for the success of treatments, i.e., 5-year OS of 66 to 74%.
Kantarjian HM, DeAngelo DJ, Stelljes M, Martinelli G, Liedtke M, Stock W, et al. Inotuzumab ozogamicin versus standard therapy for acute lymphoblastic leukemia. N Engl J Med. 2016;375(8):740–53.
Kantarjian H, Stein A, Gökbuget N, Fielding AK, Schuh AC, Ribera J-M, et al. Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia. N Engl J Med. 2017;376(9):836–47.
Turtle CJ, Hay KA, Hanafi L-A, Li D, Cherian S, Chen X, et al. Durable molecular remissions in chronic lymphocytic leukemia treated with CD19-specific chimeric antigen receptor–modified T cells after failure of ibrutinib. J Clin Oncol. 2017;35(26):3010–20.
Jones JA, Mato AR, Wierda WG, Davids MS, Choi M, Cheson BD, et al. Venetoclax for chronic lymphocytic leukaemia progressing after ibrutinib: an interim analysis of a multicentre, open-label, phase 2 trial. Lancet Oncol. 2018;19(1):65–75.
Krämer I, Stilgenbauer S, Dietrich S, Böttcher S, Zeis M, Stadler M, et al. Allogeneic hematopoietic cell transplantation for high-risk CLL: 10-year follow-up of the GCLLSG CLL3X trial. Blood. 2017;130(12):1477–80.
Jensen MC, Popplewell L, Cooper LJ, DiGiusto D, Kalos M, Ostberg JR, et al. Antitransgene rejection responses contribute to attenuated persistence of adoptively transferred CD20/CD19-specific chimeric antigen receptor redirected T cells in humans. Biol Blood Marrow Transplant. 2010;16(9):1245–56.
•• Gardner R, Wu D, Cherian S, Fang M, Hanafi L-A, Finney O, et al. Acquisition of a CD19-negative myeloid phenotype allows immune escape of MLL-rearranged B-ALL from CD19 CAR-T-cell therapy. Blood. 2016;127(20):2406–10 Study showing target antigen loss is a key method of therapeutic escape.
Kantarjian HM, O’Brien S, Smith TL, Cortes J, Giles FJ, Beran M, et al. Results of treatment with hyper-CVAD, a dose-intensive regimen, in adult acute lymphocytic leukemia. J Clin Oncol. 2000;18(3):547–7.
Sureda A, Bader P, Cesaro S, Dreger P, Duarte RF, Dufour C, et al. Indications for allo- and auto-SCT for haematological diseases, solid tumours and immune disorders: current practice in Europe, 2015. Bone Marrow Transplant. 2015;50(8):1037–56.
Majhail NS, Farnia SH, Carpenter PA, Champlin RE, Crawford S, Marks DI, et al. Indications for autologous and allogeneic hematopoietic cell transplantation: guidelines from the American Society for Blood and Marrow Transplantation. Biol Blood Marrow Transplant. 2015;21(11):1863–9.
Faderl S, O’Brien S, Pui C-H, Stock W, Wetzler M, Hoelzer D, et al. Adult acute lymphoblastic leukemia. Cancer. 2010;116(5):1165–76.
Issa GC, Kantarjian HM, Yin C, Cameron QW, Farhad R, Deborah T, et al. Prognostic impact of pretreatment cytogenetics in adult Philadelphia chromosome–negative acute lymphoblastic leukemia in the era of minimal residual disease. Cancer. 2017;123(3):459–67.
Brüggemann M, Schrauder A, Raff T, Pfeifer H, Dworzak M, Ottmann OG, et al. Standardized MRD quantification in European ALL trials: Proceedings of the Second International Symposium on MRD assessment in Kiel, Germany, 18–20 September 2008. Leukemia. 2010;24(3):521–35.
Schrappe M. Detection and management of minimal residual disease in acute lymphoblastic leukemia. ASH Educ Program Book. 2014;2014(1):244–9.
• Tavernier E, Boiron J-M, Huguet F, Bradstock K, Vey N, Kovacsovics T, et al. Outcome of treatment after first relapse in adults with acute lymphoblastic leukemia initially treated by the LALA-94 trial. Leukemia. 2007;21(9):1907–14.
• Kantarjian HM, Thomas D, Ravandi F, Faderl S, Jabbour E, Garcia-Manero G, et al. Defining the course and prognosis of adults with acute lymphocytic leukemia in first salvage after induction failure or short first remission duration. Cancer. 2010 116(24):5568–5574. References 32 and 33 provide benchmarks for outcomes of experimental therapies for relapsed/refractory ALL.
Fielding AK, Richards SM, Chopra R, Lazarus HM, Litzow MR, Buck G, et al. Outcome of 609 adults after relapse of acute lymphoblastic leukemia (ALL); an MRC UKALL12/ECOG 2993 study. Blood. 2007;109(3):944–50.
Haso W, Lee DW, Shah NN, Stetler-Stevenson M, Yuan CM, Pastan IH, et al. Anti-CD22–chimeric antigen receptors targeting B-cell precursor acute lymphoblastic leukemia. Blood. 2013;121(7):1165–74.
Brudno JN, Kochenderfer JN. Chimeric antigen receptor T-cell therapies for lymphoma. Nat Rev. Clin Oncol. 2018;15(1):31–46.
Kato K, Miyamoto T, Yonemoto K, Uchida N, Ogawa H, Fukuda T, et al. Second allogeneic hematopoietic stem cell transplantation (allo-HSCT) for relapse of hematological malignancies after first allo-HSCT. Blood. 2014;124(21):3947–7.
Nagler A, Labopin M, Beelen D, Ciceri F, Volin L, Shimoni A, et al. Long-term outcome after a treosulfan-based conditioning regimen for patients with acute myeloid leukemia: a report from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation. Cancer. 2017;123(14):2671–9.
Wilson WH, Young RM, Schmitz R, Yang Y, Pittaluga S, Wright G, et al. Targeting B cell receptor signaling with ibrutinib in diffuse large B cell lymphoma. Nat Med. 2015;21(8):922–6.
Gerecitano JF, Roberts AW, Seymour JF, Wierda WG, Kahl BS, Pagel JM, et al. A phase 1 study of venetoclax (ABT-199/GDC-0199) monotherapy in patients with relapsed/refractory non-Hodgkin lymphoma. Blood. 2015;126(23):254–4.
Goy A, Ramchandren R, Ghosh N, Munoz J, Morgan DS, Dang NH, et al. A multicenter open-label, phase 1b/2 study of ibrutinib in combination with lenalidomide and rituximab in patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL). Blood. 2016;128(22):473–3.
van Imhoff GW, McMillan A, Matasar MJ, Radford J, Ardeshna KM, Kuliczkowski K, et al. Ofatumumab versus rituximab salvage chemoimmunotherapy in relapsed or refractory diffuse large B-cell lymphoma: the ORCHARRD study. J Clin Oncol. 2017;35(5):544–51.
van Kampen RJW, Canals C, Schouten HC, Nagler A, Thomson KJ, Vernant J-P, et al. Allogeneic stem-cell transplantation as salvage therapy for patients with diffuse large B-cell non-Hodgkin’s lymphoma relapsing after an autologous stem-cell transplantation: an analysis of the European Group for Blood and Marrow Transplantation Registry. J Clin Oncol. 2011;29(10):1342–8.
Klyuchnikov E, Bacher U, Kroll T, Shea TC, Lazarus HM, Bredeson C, et al. Allogeneic hematopoietic cell transplantation for diffuse large B cell lymphoma: who, when and how? Bone Marrow Transplant. 2014;49(1):1–7.
Sebban C, Brice P, Delarue R, Haioun C, Souleau B, Mounier N, et al. Impact of rituximab and/or high-dose therapy with autotransplant at time of relapse in patients with follicular lymphoma: a GELA study. J Clin Oncol. 2008;26(21):3614–20.
Sebban C, Mounier N, Brousse N, Belanger C, Brice P, Haioun C, et al. Standard chemotherapy with interferon compared with CHOP followed by high-dose therapy with autologous stem cell transplantation in untreated patients with advanced follicular lymphoma: the GELF-94 randomized study from the Groupe d’Etude des Lymphomes de l’Adulte (GELA). Blood. 2006;108(8):2540–4.
Fowler NH, Davis RE, Rawal S, Nastoupil L, Hagemeister FB, McLaughlin P, et al. Safety and activity of lenalidomide and rituximab in untreated indolent lymphoma: an open-label, phase 2 trial. Lancet Oncol. 2014;15(12):1311–8.
Fowler NH, Samaniego F, Turturro F, Neelapu S, Forbes S, Westin J, et al. The immunologic doublet of lenalidomide plus obinutuzumab is highly active in relapsed/refractory follicular lymphoma, results of a phase I/II study. Hematol Oncol. 2017;35:268–9.
Gopal AK, Kahl BS, de Vos S, Wagner-Johnston ND, Schuster SJ, Jurczak WJ, et al. PI3Kδ inhibition by idelalisib in patients with relapsed indolent lymphoma. N Engl J Med. 2014;370(11):1008–18.
Zinzani PL, Topp MS, Yuen SL, Rusconi C, Fleury I, Pro B, et al. Phase 2 study of venetoclax plus rituximab or randomized VEN plus bendamustine+rituximab (BR) versus BR in patients with relapsed/refractory follicular lymphoma: interim Data. Blood. 2016;128(22):617–7.
Bartlett NL, Costello BA, LaPlant BR, Ansell SM, Kuruvilla JG, Reeder CB, et al. Single-agent ibrutinib in relapsed or refractory follicular lymphoma: a phase 2 consortium trial. Blood. 2017;1:blood-2017-09-804641.
Trněný M, Lamy T, Walewski J, Belada D, Mayer J, Radford J, et al. Lenalidomide versus investigator’s choice in relapsed or refractory mantle cell lymphoma (MCL-002; SPRINT): a phase 2, randomised, multicentre trial. Lancet Oncol. 2016;17(3):319–31.
Hess G, Herbrecht R, Romaguera J, Verhoef G, Crump M, Gisselbrecht C, et al. Phase III study to evaluate temsirolimus compared with investigator’s choice therapy for the treatment of relapsed or refractory mantle cell lymphoma. J Clin Oncol. 2009;27(23):3822–9.
Dreyling M, Morschhauser F, Bouabdallah K, Bron D, Cunningham D, Assouline SE, et al. Phase II study of copanlisib, a PI3K inhibitor, in relapsed or refractory, indolent or aggressive lymphoma. Ann Oncol. 2017;28(9):2169–78.
Kuo H-P, Ezell SA, Schweighofer KJ, Cheung LWK, Hsieh S, Apatira M, et al. Combination of ibrutinib and ABT-199 in diffuse large B-cell lymphoma and follicular lymphoma. Mol Cancer Ther. 2017;16(7):1246–56.
• Cohen AD, Garfall AL, Stadtmauer EA, Lacey SF, Lancaster E, Vogl DT, et al. B-cell maturation antigen (BCMA)-specific chimeric antigen receptor T cells (CART-BCMA) for multiple myeloma (MM): initial safety and efficacy from a phase I study. Blood. 2016;128(22):1147–7 Initial safety study of BCMA CAR-T cells.
Berdeja JG, Lin Y, Raje N, Munshi N, Siegel D, Liedtke M, et al. Durable clinical responses in heavily pretreated patients with relapsed/refractory multiple myeloma: updated results from a multicenter study of bb2121 anti-Bcma CAR T cell therapy. Blood. 2017;130(Suppl 1):740–0.
• Updated results of ongoing multicenter phase I study of bb2121 anti-BCMA CAR T cell therapy continue to demonstrate deep and durable responses in patients with late-stage relapsed/refractory multiple myeloma at ASCO Annual Meeting (NASDAQ:CELG) [Internet]. [cited 2018 Jul 18]. Available from: http://ir.celgene.com/releasedetail.cfm?releaseid=1069096. Impressive safety and efficacy data with preserved safety profile for myeloma.
• Chekmasova AA, Horton HM, Garrett TE, Evans JW, Griecci J, Hamel A, et al. A novel and highly potent CAR T cell drug product for treatment of BCMA-expressing hematological malignances. Blood. 2015;126(23):3094–3094. Evidence that BCMA CAR-T cells can recognize target cells with < 1000 copies of target antigen on their surface.
•• Perna F, Berman SH, Soni RK, Mansilla-Soto J, Eyquem J, Hamieh M, et al. Integrating proteomics and transcriptomics for systematic combinatorial chimeric antigen receptor therapy of AML. Cancer Cell. 2017;32(4):506–519.e5 Key paper illustrating the challenges of identifying suitable antigens for CAR-T cells to treat myeloid malignancies.
Fan M, Li M, Gao L, Geng S, Wang J, Wang Y, et al. Chimeric antigen receptors for adoptive T cell therapy in acute myeloid leukemia. J Hematol OncolJ Hematol Oncol. 2017;10:151.
Petrov JC, Wada M, Pinz KG, Yan LE, Chen KH, Shuai X, et al. Compound CAR T-cells as a double-pronged approach for treating acute myeloid leukemia. Leukemia. 2018;25:1.
Wang Q, Wang Y, Lv H, Han Q, Fan H, Guo B, et al. Treatment of CD33-directed chimeric antigen receptor-modified T cells in one patient with relapsed and refractory acute myeloid leukemia. Mol Ther. 2015;23(1):184–91.
Porter DL, Hwang W-T, Frey NV, Lacey SF, Shaw PA, Loren AW, et al. Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia. Sci Transl Med. 2015;7(303):303ra139–9.
Bishop DC, Xu N, Tse B, O’Brien TA, Gottlieb DJ, Dolnikov A, et al. PiggyBac-engineered T cells expressing CD19-specific CARs that lack IgG1 Fc spacers have potent activity against B-ALL xenografts. Mol Ther [Internet]. 2018 10 [cited 2018 Jul 27];0(0). Available from: https://www.cell.com/molecular-therapy-family/molecular-therapy/abstract/S1525-0016(18)30210-7.
Kebriaei P, Singh H, Huls MH, Figliola MJ, Bassett R, Olivares S, et al. Phase I trials using Sleeping Beauty to generate CD19-specific CAR T cells. J Clin Invest. 2016;126(9):3363–76.
Qasim W, Zhan H, Samarasinghe S, Adams S, Amrolia P, Stafford S, et al. Molecular remission of infant B-ALL after infusion of universal TALEN gene-edited CAR T cells. Sci Transl Med. 2017;9(374):eaaj2013.
Li Y, Hermanson DL, Moriarity BS, Kaufman DS. Human iPSC-derived natural killer cells engineered with chimeric antigen receptors enhance anti-tumor activity. Cell Stem Cell. 2018;23(2):181–192.e5.
McCurdy SR, Kasamon YL, Kanakry CG, Bolaños-Meade J, Tsai H-L, Showel MM, et al. Comparable composite endpoints after HLA-matched and HLA-haploidentical transplantation with post-transplantation cyclophosphamide. Haematologica. 2017;102(2):391–400.
Milano F, Gooley T, Wood B, Woolfrey A, Flowers ME, Doney K, et al. Cord-blood transplantation in patients with minimal residual disease. N Engl J Med. 2016;375(10):944–53.
Segal Eric, Martens Michael, Wang Hai-Lin, Brazauskas Ruta, Weisdorf Daniel, Sandmaier Brenda M., et al. Comparing outcomes of matched related donor and matched unrelated donor hematopoietic cell transplants in adults with B-cell acute lymphoblastic leukemia. Cancer. 2017;123(17):3346–3355.
Sorror ML, Maris MB, Storb R, Baron F, Sandmaier BM, Maloney DG, et al. Hematopoietic cell transplantation (HCT)-specific comorbidity index: a new tool for risk assessment before allogeneic HCT. Blood. 2005;106(8):2912–9.
Hay KA, Hanafi L-A, Li D, Gust J, Liles WC, Wurfel MM, et al. Kinetics and biomarkers of severe cytokine release syndrome after CD19 chimeric antigen receptor-modified T cell therapy. Blood. 2017;1:blood-2017-06-793141.
Turtle CJ, Hay KA, Juliane G, Hanafi L-A, Li D, Chaney C, et al. Biomarkers of cytokine release syndrome and neurotoxicity after CD19 CAR-T cells and mitigation of toxicity by cell dose. Blood. 2016;128(22):1852–2.
Shlomchik WD. Graft-versus-host disease. Nat Rev. Immunol. 2007;7(5):340–52.
Lee SJ, Logan B, Westervelt P, Cutler C, Woolfrey A, Khan SP, et al. Comparison of patient-reported outcomes in 5-year survivors who received bone marrow vs peripheral blood unrelated donor transplantation: long-term follow-up of a randomized clinical trial. JAMA Oncol. 2016;2(12):1583–9.
Dreyling M, Jurczak W, Jerkeman M, Silva RS, Rusconi C, Trneny M, et al. Ibrutinib versus temsirolimus in patients with relapsed or refractory mantle-cell lymphoma: an international, randomised, open-label, phase 3 study. Lancet. 2016;387(10020):770–8.
Funding
This work was supported by a T32 institutional training grant from the National Institutes of Health to Jacob Appelbaum (5T32HL007093).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of Interest
Jacob S. Appelbaum and Filippo Milano declare that they have no conflict of interest.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Additional information
This article is part of the Topical Collection on CART and Immunotherapy
About this article
Cite this article
Appelbaum, J.S., Milano, F. Hematopoietic Stem Cell Transplantation in the Era of Engineered Cell Therapy. Curr Hematol Malig Rep 13, 484–493 (2018). https://doi.org/10.1007/s11899-018-0476-4
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11899-018-0476-4