Donor lymphocyte infusions (DLI) are an effective treatment for patients with chronic myeloid leukemia (CML) in relapse after allografting but the optimal cell dose has yet to be identified. To address this question, we investigated the factors affecting the dose required to achieve remission (effective cell dose, (ECD)) in 81 patients treated with an escalating dose regimen. The overall proportion of patients who achieved a molecular remission was 88%. The cumulative proportion of remitters increased significantly at each dose level. With a CD3+ cell dose ⩽107/kg, 56% of patients in molecular/cytogenetic relapse obtained molecular remission, whereas only 20% of those in hematologic relapse did so. At the same cell dose, 58% of patients who received lymphocytes from volunteer unrelated donors achieved remission, as compared to 29% of those who received DLI from sibling donors. We conclude that the response to DLI is dose-dependent and that the ECD is influenced by the quantity and phase of CML at relapse and degree of donor/recipient histocompatibility.
The graft-versus-tumor effect exerted by donor lymphocytes is a major component of the therapeutic benefit that results from allogeneic stem cell transplantation (SCT). This conclusion was based originally on the observation that patients surviving acute graft-versus-host disease (GVHD) had a reduced rate of leukemia relapse1 and on the later observation that patients transplanted with marrow cells subjected to T-cell depletion to prevent GVHD had an increased rate of leukemia relapse.2 The success of lymphocyte infusions from the original stem cell donor (donor lymphocyte infusions, DLI) to treat leukemia relapse was first reported in 1990.3 Subsequently, their overall efficacy and the durability of the responses obtained in chronic myeloid leukemia (CML) were confirmed by several transplant centers worldwide and DLI were used for different types of hematologic malignancy.4, 5, 6, 7, 8, 9, 10
Among the various malignancies, CML is undoubtedly the most sensitive target for the DLI-induced graft-versus-leukemia (GVL) effect. Thus the use of DLI in this type of leukemia offers an opportunity to monitor a patient's response attributable to the GVL effect with great precision. For CML, the best responses occur in patients diagnosed or treated in cytogenetic or molecular relapse as compared to those whose relapse was detected only at hematologic level.11 Furthermore, among patients with hematologic relapse, complete remissions were more frequent in patients with chronic phase relapses than in those with CML recurring in accelerated phase or blastic transformation.5, 6, 12 Other factors predictive of response include T-cell depletion at the time of transplant,12 longer interval between transplant and diagnosis of relapse6 and the presence of donor chimerism at time of DLI.13 Although the relative importance of these factors varies in the different studies, there is general agreement that a minority of patients do not respond, but the reasons underlying this failure have not been elucidated. Although the failure of DLI in advanced phases could be attributed to the ‘rapid’ kinetic features of the leukemia population, as exemplified also in an acute leukemia, the resistance in chronic phase, observed in 29–45% of treated cases,6, 14 could be due in some patients to intrinsic insuperable resistance of leukemic cells to a general or specific GVL effect. However, the total dose of lymphocytes transfused in the various studies has been rather heterogeneous, so it remains possible that some patients who did not respond failed simply because they did not receive enough cells. Donor lymphocytes can be given as a single dose of somewhat arbitrary total numbers according to a bulk dose regimen (BDR) or in multiple doses of fixed or progressively escalating cell numbers.15 The use of an escalating dose regimen (EDR), initially reported by the transplant group at the Memorial Sloan-Kettering in New York,15 is based on the principle that the cell dose is increased progressively until remission is achieved. This approach should allow the therapeutic effect of each cell dose to be assessed.
In this analysis, we have evaluated the effective cell dose (ECD) required to achieve molecular remission and the factors influencing ECD in patients undergoing DLI according to an EDR. The analysis was carried out retrospectively in a cohort of patients with CML in molecular, cytogenetic or hematologic (chronic or accelerated phase) relapse after allogeneic SCT. Our EDR was designed such that the intervals between successive doses were long enough to allow us to attribute a given clinical response to the immediately preceding dose.
Patients and methods
Eighty-one patients were treated with escalating doses of donor lymphocytes following relapse of CML after standard conditioning allogeneic SCT (Table 1). Patients were treated at the Hammersmith Hospital between February 1996 and November 2005. On the whole, 289 patients were transplanted for CML in the 10 years of the study duration. There were 119 relapses and 91 of them received DLI. Ten out of them have been excluded from the analysis as they did not complete our DLI protocol. Since 1996 all the patients receiving DLI were treated according to an EDR. Thirty-one patients were recipients of an HLA-identical sibling transplants (SIB) and 50 of volunteer unrelated donor transplants (VUD). Seventy-one patients were transplanted in first chronic phase, nine in accelerated phase and one in second chronic phase. None of them had been previously treated with tyrosine kinase inhibitors. At the time of relapse, 38 patients were in molecular, 23 in cytogenetic, 20 in hematologic relapse (16 in chronic and four in accelerated phase). The median time between relapse and first DLI was 8.1 months (1–53). Conventional myeloablative conditioning comprising cyclophosphamide and total body irradiation and GVHD prophylaxis with cyclosporine and methotrexate were used as described previously.16, 17 Twenty patients received non-manipulated peripheral blood or marrow cells and 61 patients received donor cells treated ex vivo with anti-CD52 murine monoclonal antibody (Campath 1M) or received CD52 antibody intravenously for the prevention of GVHD (Campath 1H).17
Patients considered in remission after allogeneic SCT were monitored in the clinic at intervals not exceeding 3 months and usually more frequently. When relapse was diagnosed (see below), the frequency with which patients were monitored was increased. At each clinic visit full blood counts were performed. For patients transplanted before 1991, samples of bone marrow were aspirated regularly for cytogenetic examination. From 1991 to 2000, peripheral blood samples were studied at intervals of 1–3 months after transplant for the presence of BCR-ABL transcripts by a multiplex and/or a nested reverse transcriptase PCR.18 In January 2001, a real-time quantitative PCR was introduced.19 Results were reported as the ratio between BCR-ABL and ABL transcript numbers expressed as a percent. Patients were considered to be in continuing complete remission post-transplant if PCR studies were negative, or were positive at low level and failed to satisfy the criteria for molecular relapse defined below. If the BCR-ABL/ABL ratio was raised, cytogenetic studies were performed on bone marrow metaphases. The frequency of cytogenetic and molecular monitoring after SCT was similar for recipients of SIB and VUD transplants.
Definition of relapse
The 81 patients in this series satisfied criteria for molecular, cytogenetic or hematologic relapse at the time when treatment with DLI was initiated (Table 1). A patient was considered to be in molecular relapse if over a minimum of 4 weeks the BCR-ABL/ABL ratio exceeded 0.02% in three samples, or exceeded 0.05% in two samples, or showed rising levels with the last two higher than 0.02% as reported previously.20 Cytogenetic relapse was diagnosed if one or more Ph-positive metaphases were detected without evidence of hematologic relapse. Hematologic relapse was diagnosed in the presence of peripheral blood leukocytosis, usually with predominance of myelocytes and neutrophils in the differential count, accompanied by a hypercellular bone marrow with Ph chromosome positivity on cytogenetic analysis. The phase of CML was classified in accordance with criteria proposed by the International Bone Marrow Transplant Registry,21 but cytogenetic changes in addition to the Ph chromosome in the absence of other relevant features were not considered as diagnostic of accelerated phase disease. Patients who relapsed in blastic phase were excluded from the study because they all received chemotherapy and/or imatinib mesylate in addition to DLI.
Management of relapse with escalating dose regimen DLI
Eighty-one patients relapsed after allogeneic SCT at a median time of 8.7 months. The diagnosis of relapse was based on the molecular (n=38), cytogenetic (n=23) or hematologic (n=20) criteria defined above. In general, efforts were made to administer DLI as soon as this could conveniently be scheduled. In practice, the median interval between recognition of relapse and initiating DLI was 8.1 months. Virtually all relapses were diagnosed at a molecular and/or cytogenetic level but a proportion of patients had progressed to a hematologic relapse by the time of their first DLI. In all cases, progression occurred in patients, in which there was a technical delay in donor lymphocyte collection. None of the patients was treated on a prophylactic or preemptive basis. At the time of relapse, 27 patients were still on cyclosporine. The immunosuppressant was gradually stopped in all of them for at least 1 month before DLI. At time of relapse, only one patient was suffering of grade III skin GVHD, which was completely resolved at DLI.
Donor lymphocytes were collected by leukapheresis on a continuous blood flow cell separator (Cobe Spectra, Gloucester, UK). The dose of CD3+ cells was calculated by cytofluorimetric analysis after staining with a CD3 monoclonal antibody (Becton Dickinson, Oxford, UK). Donor lymphocytes were either administered on the same day of collection or stored in liquid nitrogen until use. All patients received lymphocytes from their original donor. Patients failing to achieve molecular remission after each infusion received an increased dose according to a previously described EDR schedule.22 In particular, patients transplanted from a sibling donor received 107 → 5 × 107 → 108 → >108 donor CD3+cells/kg, whereas patients receiving transplant from a VUD received 106 → 107 → 5 × 107 → 108 → >108 donor CD3+cells/kg. The higher dose was always >108 donor CD3+cells/kg, even though with some variability between patients, owing to the different availability of cells (median 2 × 108, range 1.5–6 × 108 CD3+cells/kg). The scheduled cell dose was administered without correction for the stage or phase of leukemia at relapse but patients in hematologic relapse were treated with hydroxyurea before DLI if their leukocyte counts exceeded 30 × 109/l. None of the patients received any other treatment for CML relapse (e.g. imatinib mesylate, interferon). In order to allow the response to each dose to be assessed, the interval between doses (except in a single case) was 12 weeks or longer, with a median of 19.6 weeks.
Assessment of response
Following DLI, PCR for BCR-ABL/ABL was performed at 4–6-week intervals. Molecular remission was defined by the absence of detectable BCR-ABL transcripts on two consecutive occasions or BCR-ABL/ABL <0.005% on two consecutive occasions. To control for sample quality in BCR-ABL-negative specimens, cDNA was considered valuable only if it contained at least 2 × 104 normal ABL transcripts/5 ml cDNA. This ensured that the absence of BCR-ABL transcripts could be excluded at a sensitivity of at least 5 × 10−5.23 Failure to respond was defined by the lack of molecular remission 1 year following the administration of a dose of 108 CD3+ cells/kg. All patients included in this report completed the full protocol, that is, they were treated until they responded or until they were deemed refractory to DLI. Acute GVHD was graded according to the Seattle criteria.24 Chronic GVHD was defined as none, limited or extensive.
Probabilities of achieving molecular remission post DLI were calculated using the cumulative incidence procedure. Comparisons between prognostic groups for molecular remission were carried out using the log-rank test. Those variables significant at the P<0.2 level in univariate analyses were further examined using proportional hazards regression analysis employing a backward stepping procedure to identify the most statistically significant model. All P-values are two-sided. Confidence intervals refer to 95% boundaries.
Overall response following DLI
Seventy-one out of 81 patients (88%) achieved molecular remission following DLI. Median time from the first DLI to remission was 8.9 months. Median time from the ECD to remission was 4.1 months. Of the 10 patients who did not achieve a complete molecular response (five SIB and five VUD), six maintained low-level PCR positivity (three have had a single PCR-negative result), one patient is multiplex positive, two patients progressed to blastic phase and died and one has been lost to follow-up.
Following infusion of escalating donor lymphocytes, acute GVHD of grade II or higher occurred in 12 patients (three SIB and nine VUD) (15%). Extensive chronic GVHD occurred in two patients who had received a SIB and 10 who had received a VUD transplant (15%); in 75% of the cases it followed acute GVHD of grade II or more. None of the patients developed grade IV GVHD and none died of GVHD. The overall survival was 92% at a median follow-up of 77 months from the first DLI.
Factors influencing response to DLI
The probabilities of achieving molecular remission after DLI were 87% for patients in molecular relapse, 95% for those in cytogenetic relapse and 75% for those with hematologic disease (P=0.01). The median time for achieving remission was 9.9, 6.2 and 24.2 months, respectively. Thus, the overall proportion of responders and the time to achieve remission were influenced by the disease stage (Figure 1). This finding implies not only that patients with more sizeable disease are less responsive to treatment but also that they require higher doses of DLI to obtain remission. Overall remission rates (90 versus 84%), as well as median times to molecular remission (8.7 versus 13.7 months) were similar for recipients of VUD and SIB transplants. We also analyzed the possible impact on response to DLI of several other factors (donor–recipient sex mismatch, post-DLI acute GVHD, T-cell depletion at time of SCT, interval between either SCT or relapse and first DLI, patient age at time of DLI), none of which turned out to be statistically significant. Surprisingly, CMV seropositivity, regardless of whether it affected donor or recipient or both, had a negative influence on the remission rate (P=0.022). The significance of CMV status and disease status at time of DLI as independent factors was confirmed in a Cox regression analysis (data not shown).
DLI is subject to a dose–response effect
Patients deemed as failing to achieve molecular remission after each infusion, received an increased dose according to the EDR described above. Each infusion increased the proportion of responders (Table 2). In patients transplanted from a SIB donor, the percentages of cumulative responders to cell doses of 107, 5 × 107, 108 and >108 CD3+ donor cells/kg were 29, 45, 65 and 84%, respectively. In patients receiving a VUD transplant, the percentages of cumulative responders to cell doses of 106, 107, 5 × 107, 108 and >108 CD3+ donor cells/kg were 26, 58, 80, 86 and 90%, respectively.
Factors affecting effective cell dose
When patients who received their graft from a VUD or a SIB donor were compared, the ECD was lower in the former group. In fact, among patients receiving a dose ⩽107 CD3+ cells/kg, the proportion of responders was 58% in the VUD group as compared to 29% among the SIB recipients (P=0.015) (Table 3). However, VUD recipients were started at a lower initial cell dose, thus receiving one more dose than SIB recipients below the 107 CD3+ cells/kg cutoff. The ECD was also influenced by the disease stage at time of DLI: a dose of 106–107 CD3+ cells/kg was sufficient to restore molecular remission in 56% of patients in molecular or cytogenetic relapse but in only 20% of patients in hematologic relapse (P=0.037) (Table 4).
Acute GVHD of grade II or more developed in 12 patients. All infusions resulting in grade II–IV aGVHD (12/12) also produced molecular remission, whereas 30% of the infusions (59/198) resulting in grade 0–I aGVHD did so. Therefore, the cell dose resulting in acute GVHD of grade II or more, when this occurred, was also the ECD.
Eleven patients (two SIB and nine VUD) (15%) relapsed after achieving complete molecular remission following DLI. Of these, nine received further DLI infusions: six patients returned to complete molecular remission and three maintained low-level persistent PCR positivity. One progressed to blastic phase and died, and one patient is receiving treatment with imatinib and has returned to molecular remission. Remission with further DLI infusions was achieved when a higher cell dose was given. This suggests that leukemia cells do not acquire resistance to DLI with the passage of time even though a higher cell dose is required to achieve remission.
The current approach to administration of DLI is based on the use of escalating cell doses until a response is achieved. In principle, it would be desirable to know the ECD for each patient but the variability of patient features in the published studies does not permit this analysis. We evaluated the ECD in 81 CML patients in molecular, cytogenetic or hematologic (chronic or accelerated phase) relapse after transplant, who received DLI according to our EDR.22 The long interval between infusions allowed each dose to be classified as effective or ineffective on the basis of studies that assessed the kinetics of response after DLI.25
The large number of responders using our EDR suggests that most CML patients can achieve molecular remission, provided that sufficient numbers of donor lymphocytes are infused. In fact, the cumulative number of responders increased at each dose level, thus demonstrating that DLI is subject to a dose–response effect. Furthermore, if we re-examine our previously published results, the probability of achieving remission is substantially higher with the EDR as compared to the BDR (67%),22 even when comparing patients treated at the same disease stage (data not shown). The difference could well be attributed to the overall number of cells administered to the patients, which was higher in the EDR group. Considering that the number of cell doses is proportional to the interval between the initial dose and the possible molecular response, one might speculate that the time after the first administrations rather than the dose escalation is the most relevant factor responsible for the increase in the cumulative response rates. However, the fact that in no case the interval between the ECD and remission was less than 6 weeks (data not shown), clearly argues against this hypothesis, demonstrating the consistent inefficacy of the administrations preceding the dose closer to the molecular remission. This concept has important implications for the definition of refractoriness to DLI and the use of an EDR. Our data strongly suggest that the donor lymphocyte dose for patients who have not yet responded should be increased indefinitely, because by stopping escalation prematurely potential responders may be missed.
When we examined the variables affecting the ECD, a major factor was disease stage. In fact, a cell dose of 106–107 donor CD3+ cells/kg was sufficient to restore molecular remission in 56% of patients in molecular or cytogenetic relapse but only in 20% of patients in hematologic relapse. This suggests that the larger the tumor burden, the greater the number of cells required to restore remission. As in most of the cases the DLI effect is an all-or-nothing phenomenon, great caution should be exercised before defining as non-responders patients with disease in hematologic relapse who have not responded to low or moderate cell doses. In the absence of GVHD, these patients should continue their treatment with higher doses. One cannot ignore the possibility that patients with CML in blastic phase, until now considered to respond very poorly to DLI, might be amenable to benefit of the treatment if the cell dose were high enough to control the large bulk of leukemic cells. In fact, in cases of full-blown blastic transformation the number of targetable leukemia stem cells with self-renewal capacity may be much greater than those present in the chronic phase of CML.26 Similarly, other disease types resistant or poorly sensitive to DLI4, 10, 27 might be treated successfully provided that the optimal ECD were identified.
Another important factor to be taken into consideration is donor type. At the same disease stage, VUD recipients responded to a lower dose as compared to SIB recipients. The differing potency of cells from different donor types probably reflects the frequency of alloreactive T-cell precursors,28 as a consequence of the larger disparity between donor and recipient at the level of minor histocompatibility antigens.29 However, it should be taken into account that VUD recipients were started at a lower initial cell dose than patients receiving their SCT from a SIB donor. Therefore, it is not possible to completely exclude that this difference was at least partially due to the administration of an additional cell dose in the former group below the 107 CD3+ cells/kg cutoff.
Although the presence of a small disease burden at relapse after SCT is potentially the optimal situation for the use of imatinib, DLI still seems to play a major role in this scenario. In a series of 128 CML patients relapsed after SCT, despite an overall hematological response rate of 84%, complete molecular responses were obtained in only 26% of patients.30 Moreover, a recent retrospective study compared the clinical outcome in a small group of CML patients who had received DLI or imatinib for relapse after SCT and showed that, although the proportion of responders did not statistically differ, imatinib was associated to a higher incidence of relapse and inferior leukemia-free survival.31 Patients with CML relapsing after SCT were recently studied for the therapeutic efficacy of the combination of DLI with imatinib. Even though the data are obtained retrospectively and based on a small group of patients, the association regimen appeared to offer some advantage in terms of rapidity of remission as well as of actuarial overall and disease free survival, especially in patients in accelerated phase.32 If confirmed, this result could be particularly relevant for patients relapsing in advanced stage disease, who respond poorly to either DLI or imatinib alone.
In conclusion, DLI treatment for CML is highly efficacious, if an appropriate number of cells is administered. We have observed that the ECD of DLI depends on the number of leukemic cells at time of DLI and on the alloreactive T cell precursor frequency contained in the donor lymphocyte preparation.
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This work was partly supported by the Leukemia Research Fund. C Fozza is the recipient of the fellowship ‘Master and back TS 07’ offered by Regione Autonoma della Sardegna.
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Simula, M., Marktel, S., Fozza, C. et al. Response to donor lymphocyte infusions for chronic myeloid leukemia is dose-dependent: the importance of escalating the cell dose to maximize therapeutic efficacy. Leukemia 21, 943–948 (2007). https://doi.org/10.1038/sj.leu.2404641
- donor lymphocyte infusions
- chronic myeloid leukemia
- effective cell dose
- escalating dose regimen
- allogeneic stem cell transplantation
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