T-cell depletion plus salvage immunotherapy with donor leukocyte infusions as a strategy to treat chronic-phase chronic myelogenous leukemia patients undergoing HLA-identical sibling marrow transplantation.

T-cell depletion (TCD) of the donor marrow graft has been shown to reduce the severity of graft-versus-host disease (GVHD) in patients with chronic-phase (CP) chronic myelogenous leukemia (CML) undergoing HLA-identical sibling allogeneic marrow transplantation. However, there has been a corresponding reduction in the graft-versus-leukemia effect so that any decrease in GVHD-related mortality has been offset by an increased rate of disease relapse. Therapy of recurrent disease with donor leukocyte infusions (DLI) has been proven to be effective salvage therapy for the majority of patients who relapse after allogeneic BMT with CP CML. However, the overall impact of salvage DLI therapy on the survival of CP CML patients initially transplanted with TCD marrow grafts is not defined. To address this question, we have evaluated a clinical strategy of TCD followed by targeted adoptive immunotherapy with DLI in 25 CP CML patients undergoing allogeneic BMT from HLA-identical siblings. All patients received a standardized preparative regimen along with ex vivo TCD and posttransplant cyclosporine as GVHD prophylaxis. Durable engraftment was observed in all 25 patients. The incidence of grade II to IV acute GVHD was 8%. The cumulative incidence of transplant-related mortality (TRM) was 4%, and the 1-year probability of overall survival was 96%. The 3-year cumulative relapse incidence was 49%. All relapsed patients received DLI to reinduce remission. The total T-cell dose administered to these patients varied from 0.1 to 5.0 x 10(8) T cells/kg. Complete responses were observed in 12 of 14 patients, with 1 additional patient still too early to evaluate. Three patients died of GVHD after DLI, and 1 relapsed into blast crisis after a transient cytogenetic remission. Of the remaining 10 patients, 8 are in molecular remission, 1 is alive in relapse, and 1 is receiving DLI treatment. The median follow-up after infusion of surviving DLI patients in remission is 5.3 years. The probability of overall 5-year survival for the entire population is 80%, with a median follow-up of 6.4 years. We conclude that the clinical strategy of TCD followed by targeted adoptive immunotherapy with DLI for those patients with evidence of recurrent disease is a viable transplant strategy for CP CML, resulting in 80% survival and a low risk of acute GVHD and transplant-related mortality.     

Individually adjusted prophylactic donor lymphocyte infusions after CD34-selected allogeneic peripheral blood stem cell transplantation.

T cell depletion of the graft increases graft failure and relapse rate in allogeneic PBSC transplantation. Delayed lymphocyte add-back after T cell-depleted transplants might prevent these complications. We present 22 consecutive allogeneic PBSC transplants from related histocompatible donors with positive selection of CD34+ cells. Recipients received prophylactic donor lymphocyte infusions (DLI) depending on their risk of relapse and of developing GVHD. Patients were considered at high risk of relapse with AML > first CR, ALL > second CR, and CML in accelerated or blastic phase. Patients were considered at high risk of developing GVHD if older than 35 years, or with a donor sensitized through previous pregnancy or blood transfusion. Patients at high risk of relapse and low risk of GVHD were scheduled to receive three DLI. Patients at low risk of relapse and high risk of GVHD did not receive DLI. The remaining patients were scheduled to receive two DLI. The DLI were administered on days +28 (2 x 10(5)/kg), +60 (2 x 10(5)/kg) and +90 (2 x 10(6)/kg) after transplant. G-CSF mobilized peripheral stem cells from healthy donors were positively selected by an immunomagnetic method. The mean CD34+ cells and CD3+ cells infused were 4.4 x 10(6)(range 1.9-10.6) and 0.085 x 10(5) (range 0.01-0.67). Cyclosporin A was given to prevent GVHD. All the patients engrafted. Twenty-two prophylactic DLI were performed in 12 patients: seven developed acute GVHD (one case grade III-IV) and none presented pancytopenia. At a mean follow-up of 585 days (range 89-1103), 14 patients were alive in CR, one patient was alive in relapse, four patients had died of relapse and three had died of transplant-related complication. Individually adjusted prophylactic DLI at the doses we used with an escalating schedule allowed an acceptable GVHD rate and a good engraftment of donor hematopoiesis.     

Donor lymphocyte infusion and methotrexate for immune recovery after T‐cell depleted haploidentical transplantation

CD34+ cell selection minimizes graft‐versus‐host disease (GVHD) after haploidentical donor stem cell transplant but is associated with slow immune recovery and infections. We report a Phase I/II study of prophylactic donor lymphocyte infusion (DLI) followed by methotrexate (MTX) GVHD prophylaxis after CD34‐selected haploidentical donor transplant. A prophylactic DLI was given between day +30 and +42. Rituximab was given with DLI for the last 10 patients. The goal of the study was to determine a DLI dose that would result in a CD4+ cell count > 100/µL at Day +120 in ≥ 66% of patients with ≤ 33% grade II‐III, ≤ 17% grade III, and no grade IV acute GVHD by Day +180. Thirty‐five patients with malignant (n = 25) or nonmalignant disease (n = 10) were treated after CD34‐selected haploidentical donor peripheral blood stem cell transplant. The DLI dose of 5 × 10⁴/kg met the CD4/GVHD goal with 67% of patients having CD4+ cells > 100/µL and 11% grade II‐IV acute GVHD. The cumulative incidence of chronic GVHD was 16%. Fatal viral and fungal infections occurred in 11%. The 2 year estimated overall survival was 69% and the relapse rate was 14% for patients in remission at transplant. There was no effect of NK alloreactivity on relapse. Nine of ten patients at the target DLI dose cohort of 5 × 10⁴/kg are alive with median follow‐up of 18 mos (range 6‐29). Delayed prophylactic DLI and MTX was associated with promising outcomes at the target DLI dose. This trial was registered at clinicaltrials.gov , # NCT01027702.     

T-cell--depleted allogeneic bone marrow transplantation followed by donor lymphocyte infusion in patients with multiple myeloma: induction of graft-versus-myeloma effect

Previous trials of allogeneic bone marrow transplantation (BMT) in patients with multiple myeloma (MM) have demonstrated high response rates but also high transplantation-related mortality (TRM) and high relapse rates. Exploitation of this strategy remains of interest because donor lymphocyte infusions (DLIs) can induce a potent graft-versus-myeloma (GVM) effect. CD6 T-cell--depleted allogeneic BMT was combined with prophylactic CD4(+) DLI administered 6 to 9 months after BMT in an effort to reduce TRM and to induce a GVM response after BMT. Twenty-four patients with matched sibling donors and chemotherapy-sensitive disease underwent BMT. CD6 T-cell depletion of donor bone marrow was the sole method of graft-versus-host disease (GVHD) prophylaxis. GVHD after BMT was minimal, 1 (4%) grade III and 4 (17%) grade II GVHD. Fourteen patients received DLI, 3 in complete response and 11 with persistent disease after BMT. Significant GVM responses were noted after DLI in 10 patients with persistent disease, resulting in 6 complete responses and 4 partial responses. After DLI, 50% of patients developed acute (> or = II) or extensive chronic GVHD. Two-year estimated overall survival and current progression-free survival (PFS) for all 24 patients is 55% and 42%, respectively. The 14 patients receiving DLI had an improved 2-year current PFS (65%) when compared with a historical cohort of MM patients who underwent CD6-depleted BMT survived 6 months with no GVHD and did not receive DLI (41%) (P =.13). Although this study suggests that prophylactic DLI induces significant GVM responses after allogeneic BMT, only 58% of patients were able to receive DLI despite T-cell--depleted BMT. Therefore, less toxic transplantation strategies are needed to allow a higher proportion of patients to receive DLI and the benefit from the GVM effect after transplantation. (Blood. 2001;98:934-939)     

Stable mixed chimerism after T cell-depleted allogeneic hematopoietic stem cell transplantation using conditioning with low-dose total body irradiation and fludarabine

Although reduced intensity conditioning (RIC) before allografting is associated with low treatment-related morbidity and mortality, graft-versus-host disease (GVHD) remains a significant complication of hematopoietic stem cell transplantation (HSCT). T cell depletion (TCD) has been successfully used in conventional allotransplantation to reduce the incidence of GVHD, but was associated with an increased rate of engraftment failure. In a small cohort of six patients at high risk of developing GVHD we have determined whether sustained engraftment could be achieved using reduced intensity conditioning and T cell depletion in combination. All patients engrafted and 5/6 developed high levels (i.e. > or =95%) of donor chimerism, even though mismatched related or matched unrelated donors were used. Only one patient developed acute GVHD, as he received donor lymphocyte infusions (DLI) for relapse. In summary, TCD might be a useful prophylactic tool in RIC allogeneic HSCT. Although TCD after RIC might be associated with high relapse rate, as 5/6 patients are not in remission, this combined strategy might be appropriate for patients with less aggressive malignant or non-malignant diseases in which high transplant-related morbidity and mortality is not acceptable.     

Immune haemolytic anaemia following T cell-depleted allogeneic bone marrow transplantation for chronic myeloid leukaemia: association with leukaemic relapse and treatment with donor lymphocyte infusions

Immune haemolytic anaemia (IHA) is a recognised complication after allogeneic stem cell transplantation (SCT) and occurs more frequently if marrow cells have been subjected to T cell depletion (TCD). Among 58 consecutive patients who underwent TCD-allogeneic SCT from volunteer unrelated donors for the treatment of CML at the Hammersmith Hospital during a 3-year period (1 March 1996 to 28 February 1999) we identified nine cases of IHA. All patients had a strongly positive direct and indirect antiglobulin test and in eight patients the serological findings were typical of warm-type haemolysis often with antibody specificities within the Rh system. All nine cases had clinically significant haemolysis and were treated initially with prednisolone and immunoglobulin. The onset of IHA coincided with the occurrence of leukaemic relapse in six cases, and the presence of host haemopoiesis confirmed by lineage-specific chimerism in all four cases studied. Five patients received donor lymphocyte infusions (DLI); in three molecular remission and the restoration of full donor chimerism coincided with resolution of haemolysis. We conclude that in the context of leukaemic relapse, DLI is an effective therapy for IHA following allografts involving TCD.     

Outcome and long-term follow-up of alloreactive donor lymphocyte infusions given for relapse after myeloablative allogeneic hematopoietic stem cell transplantations (HSCT)

In order to study efficacy, toxicity and the long-term results of donor lymphocyte infusions (DLI), we retrospectively analyzed DLI given for relapse after conventional allogeneic hematopoietic stem cell transplantation (HSCT) in 30 patients with a median delay of 107.5 months after transplant and 58 months after DLI. After DLI, 15 patients established full donor chimerism, three patients developed grade III and one grade IV acute GVHD. A total of 15 patients achieved a disease response. Among the 14 patients with chronic myeloid leukemia (CML), 11 are alive at the last follow-up: five are in complete molecular response (CMR) and two in complete cytogenetic response (CCR) with no other intervention after DLI, three in CMR after imatinib mesylate given after DLI and one in complete hematological response after imatinib mesylate and reduced-intensity conditioning allogeneic SCT performed after DLI. At the time of the last follow-up, 19 (63%) patients died and 11 (37%) remain alive. The 3-year probability of survival for the entire population, CML patients and non-CML patients, was 60, 93, 62% after transplantation, and 48, 80 and 48% after DLI, respectively. A multivariate analysis demonstrated a significantly worse survival rate after transplantation for female recipients, advanced disease and acute leukemia before transplantation.     

Comparison of T-cell-depleted and non-T-cell-depleted unrelated donor transplantation for hematologic diseases: clinical outcomes,quality of life,and costs

T-cell depletion (TCD) and immunosuppressive medications (ISTs) are 2 methods used for graft-versus-host disease (GVHD) prophylaxis in unrelated donor (URD) transplantation. However, comparisons of the clinical outcomes including quality of life and direct medical costs associated with each type of procedure have not been reported. We reviewed 48 TCD and 98 IST procedures performed from 1/1/97 to 12/31/99 at the Dana-Farber Cancer Institute, Boston, MA. With a median follow-up of 1.5 years for survivors, no differences were seen in relapse, acute GVHD, and overall survival between TCD and IST patients. Multivariable Cox modeling showed that age of 50 years or less (P =.002) and low-risk disease (P =.001) predicted survival, but method of GVHD prophylaxis (P =.6) and degree of human leukocyte antigen (HLA) matching (P =.8) did not. A subset of patients (53%) completed quality of life surveys prior to and at 6 and 12 months after transplantation; participation in the quality of life study was not associated with clinical characteristics and outcomes. No differences were seen in quality of life scores prior to transplantation, and changes over time were similar between groups. Costs ($113 000 vs $155 000, P <.0001) and total hospital days (34 vs 46, P =.0006) were significantly lower for patients undergoing TCD procedures. As prospective, randomized studies comparing methods of GVHD prophylaxis are performed, assessment of quality of life and costs should be included to fully understand the overall impact of each intervention.     

Donor lymphocyte infusion for relapsed chronic myelogenous leukemia: prognostic relevance of the initial cell dose

Donor lymphocyte infusion (DLI) can produce durable remissions in patients with chronic myelogenous leukemia (CML) who have a relapse after an allogeneic stem cell transplantation. However, the best modality to administer DLI is still unclear. The effect of the initial cell dose (ICD; ie, mononuclear cells x 10(8)/kg received in the first instance) on outcome was retrospectively analyzed in 298 of 344 patients treated with DLI at 51 centers. Patients were classified into 3 groups according to the ICD: 98 in group A ( 2.0). Additional infusions were given to 62%, 20%, and 5% of patients in groups A, B, and C, respectively. A lower ICD was associated with less graft-versus-host disease (GVHD; A, 26%; B, 53%; C, 62%; P <.001), less myelosuppression (A, 10%; B, 23%; C, 24%; P =.01), and similar response rate (A, 78%; B, 73%; C, 70%; P =.48). Nonadjusted estimates of 3-year survival, failure-free survival, and DLI-related mortality were 84%, 66%, and 5% respectively, in group A; 63%, 57%, and 20% in group B; and 58%, 45%, and 22% in group C. Outcome analysis was adjusted for patient age, donor type, sex of donor, sex mismatch, disease phase at transplantation, T-cell depletion, interval from transplantation to DLI, GVHD prior to relapse, relapse type, and date of DLI. After adjustment, lower ICD was associated with less GVHD, less myelosuppression, same response rate, better survival, better failure-free survival, and less DLI-related mortality. Our results suggest that the first DLI dose should not exceed 0.2 x 10(8) mononuclear cells/kg.     

Graft-versus-leukemia effect in hematopoietic stem cell transplantation for pediatric acute lymphoblastic leukemia: significantly lower relapse rate in unrelated transplantations

To determine graft-versus-leukemia (GVL) effect after hematopoietic stem cell transplantation (HSCT), we studied the outcome of consecutive children with acute lymphoblastic leukemia (ALL) who received fully matched marrow allografts comparing relapse rate post HSCT between matched sibling donor (MSD) and matched unrelated donor (MUD) recipients. Furthermore, we estimated event-free survival (EFS) on the basis of the occurrence of acute graft-versus-host disease (aGVHD). Between 1998 and 2006 we performed 37 fully MSD and 36 fully MUD HSCTs. All patients received identical conditioning regimens with cyclophosphamide/total body irradiation and dual GVHD prophylaxis with cyclosporine (CSA) and methotrexate (MTX). Three-year cumulative incidence of relapse for the MSD and MUD groups were 55.6+/-12.3 and 22.0+/-8.1%, respectively (P=0.03). Three-year EFS according to aGVHD was 32.7+/-12.2% for no aGVHD, 61.2+/-10.0% for grade I-II aGVHD and 66.7+/-11.1% for grade III-IV aGVHD. Three-year EFS and overall survival (OS) were 40.5+/-11.6, 49.1+/-9.5% for the MSD group, and 60.5+/-8.7, 62.3+/-8.4% for the MUD group. In children with ALL receiving dual GVHD prophylaxis, relapse rate is significantly higher among recipients of MSD compared to MUD transplantation, which may in part be attributed to a better GVL effect with the unrelated graft.     

The long-term outcome of reduced-intensity allogeneic stem cell transplantation from a matched related or unrelated donor,or haploidentical family donor in patients with leukemia: a retrospective analysis of data from the China RIC Cooperative Group

This study compared 6-year follow-up data from patients undergoing reduced-intensity conditioning (RIC) transplantation with an HLA-matched related donor (MRD), an HLA-matched unrelated donor (MUD), or an HLA-haploidentical donor (HID) for leukemia. Four hundred and twenty-seven patients from the China RIC Cooperative Group were enrolled, including 301 in the MRD, 79 in the HID, and 47 in the MUD groups. The conditioning regimen involved fludarabine combined with anti-lymphocyte globulin and cyclophosphamide. Graft-versus-host disease (GVHD) prophylaxis was administered using cyclosporin A (CsA) and mycophenolate mofetil (MMF). Four hundred and nineteen patients achieved stable donor chimerism. The incidence of stage II-IV acute GVHD in the HID group was 44.3 %, significantly higher than that in the MRD (23.6 %) and MUD (19.1 %) groups. The 1-year transplantation-related mortality (TRM) rates were 44.3, 17.6, and 21.3, respectively. Event-free survival (EFS) at 6 years in the HID group was 36.7 %, significantly lower than that of the MRD and MUD groups (59.1 and 66.0 %, P?<?0.001 and P?=?0.001, respectively). For advanced leukemia, the relapse rate of the HID group was 18.5 %, lower than that of the MRD group (37.5 %, P?=?0.05), but the EFS at 6 years was 31.7 and 30.4 % (P?>?0.05), respectively. RIC transplantation with MRD and MUD had similar outcome in leukemia which is better than that with HID. RIC transplantation with HID had lower relapsed with higher TRM and GVHD rate, particularly in advanced leukemias. RIC transplantation with MRD and MUD had similar outcomes in leukemia and they were better than those with HID. RIC transplantation with HID had a lower relapse rate but higher TRM and GVHD rates, particularly in cases of advanced leukemia.     

Prophylactic donor lymphocyte infusions after moderately ablative chemotherapy and stem cell transplantation for hematological malignancies: high remission rate among poor prognosis patients at the expense of graft-versus-host disease

We investigated the use of 'prophylactic' donor lymphocyte infusions (DLI) containing 1 x 107 CD3+ cells, given at 30, 60 and 90 days post-allogeneic blood and marrow transplantation (BMT), following conditioning with fludarabine 30 mg/m(2)/4 days and melphalan 70 mg/m(2)/2 days. GVHD prophylaxis consisted of cyclosporin A (CsA) 2 mg/kg daily with early tapering by day 60. Our goals were the rapid achievement of chimerism and disease control, providing an immunological platform for DLIs to treat refractory patients with hematological malignancies. Twelve heavily pre-treated patients with life expectancy less than 6 months were studied; none were in remission. Diagnoses were AML (n = 4), MDS (n = 1), ALL (n = 3), CML (n = 3) and multiple myeloma (n = 1). Response rate was 75%. Three patients are alive at a median of 450 days (range, 450-540). Two patients are in remission of CML in blast crisis and AML for more than 14 months. Median survival is 116 days (range, 25-648). Six patients received 12 DLIs; three patients developed acute GVHD after the first infusion and were excluded from further DLIs, but no GVHD occurred among patients receiving subsequent DLIs. One patient with CML in blast crisis went into CR after the first DLI. The overall incidence of acute GVHD was 70%. Primary causes of death were infections (n = 3), acute GVHD (n = 3), chronic GVHD (n = 1) and disease relapse (n = 2). We observed high response and chimerism rates at the expense of an excessive incidence of GVHD. DLI given at day +30 post BMT caused GVHD in 50% of the patients, and its role in this setting remains unclear.     

Donor lymphocyte infusion for the treatment of leukemia relapse after HLA-mismatched/haploidentical T-cell-replete hematopoietic stem cell transplantation

In this study, we tested the efficacy and safety of donor lymphocyte infusion (DLI) with granulocyte colony-stimulating factor (G-CSF) priming in patients who relapsed after haploidentical hematopoietic stem cell transplantation (HSCT). Twenty patients received DLI at a median of 177 days after HSCT. Eight patients survived in complete remission for a median of 1118 days. The 2-year probability of leukemia-free survival was 40%. Acute graft-versus-host disease (GVHD) grade 3-4 occurred in six patients after DLI. GVHD prophylaxis reduced the incidence of acute GVHD. Our primary data showed that G-CSF-primed DLI with GVHD prophylaxis was a potentially effective therapeutic option for patients who relapsed after haploidentical HSCT.     

Allogeneic bone marrow transplantation

The probability of long term survival for allogeneic graft patients was 63% for ALL, 64% for ANL and 40% for CML in the 1st remission or 1st chronic phase of each leukemia. The major causes of death were interstitial pneumonia, relapse of leukemia and infections. On relationship of GVHD and the long term survival, the probability of 5 years survival was 38%, 47% and 25% in grade O, I and II-IV of acute GVHD respectively. And the relationship between the relapse rate and GVHD, the patients with both of acute and chronic GVHD showed the lowest relapse rate 15.9%, the patients without GVHD showed the highest relapse rate 37.8% and the patients with either of GVHD showed the rate of between those of two groups. This may suggest that GVHD both acute and chronic might have an ability that can suppress the relapse of leukemia, i.e. GVL reaction. Interstitial pneumonia occurred in 32% of allograft patients and was often lethal complication (53%). Among many of prophylaxis tested, the followings were effective, a lower dose rate of total body irradiation, the selection of CMV-seronegative platelets donor, and the prophylactic administration of anti-CMV high titer globulin. Colony stimulating factor of human urine was also effective for shortening the granulopenic period after transplantation to prevent severe infections.     

Posttransplantation imatinib as a strategy to postpone the requirement for immunotherapy in patients undergoing reduced-intensity allografts for chronic myeloid leukemia

Disease relapse is a major cause of treatment failure after reduced-intensity allografts and while donor lymphocyte infusions (DLIs) can be effective salvage therapy they are associated with severe graft-versus-host disease (GVHD) when administered early after transplantation. We have therefore examined whether imatinib mesylate can delay relapse and postpone the requirement for DLI in 22 patients with chronic myeloid leukemia (CML) allografted using a reduced-intensity regimen. Imatinib was commenced on day + 35 and continued until 1 year after transplantation. Posttransplantation imatinib was well tolerated and abolished the risk of relapse during this period. Twenty-one patients completed 11 months of imatinib therapy, 15 of whom subsequently relapsed and received DLI. Ten patients to date have achieved molecular remission after DLI. Adjunctive targeted therapy allows the kinetics of disease relapse after a reduced-intensity allograft to be manipulated and represents a novel strategy by which outcome may be improved in patients who undergo transplantation for CML and other leukemias.     

Allogeneic stem cell transplantation for patients with chronic myeloid leukemia: Risk stratified approach with a long-term follow-up

The use of allogeneic stem cell transplantation (SCT) for chronic myeloid leukemia (CML) was almost abandoned in recent years for very effective targeted therapy with tyrosine kinase inhibitors (TKIs). However, approximately one third of patients still need another treatment including SCT. 38 consecutive CML patients were treated (most in preimatinib era) with allogeneic SCT, using partial T cell depletion (TCD) and preemptive donor lymphocyte infusion (DLI), without post‐transplant graft‐versus‐host disease (GvHD) prophylaxis. Conditioning included busulfan, cyclophosphamide, antithymocytic globulin, and fludarabine followed by donor stem cell transfusion. With a median follow up of 90.5 months (1–134), 32 patients are alive. 97% engrafted. 5‐year leukemia free survival (LFS) and overall survival (OS) were 78.95% and 84.2%, respectively. All patients are in major molecular remission and 78% in complete molecular remission. Transplant‐related mortality (TRM) was 13%. Twenty‐four patients received DLI for residual disease. Acute GvHD, mostly Grades I‐II, occurred in 18% of patients post‐transplant and in 24% of patients receiving DLI. In conclusion, the risk‐adapted approach using only partial TCD and preemptive escalated dose of DLI precluded the need for immunosuppressive medications and reduced the risk of significant GvHD without compromising engraftment and long‐term disease control. Am. J. Hematol. 2012. © 2012 Wiley Periodicals, Inc.     

Treatment of adult acute lymphoblastic leukemia with allogeneic bone marrow transplantation. Multivariate analysis of factors affecting acute graft-versus-host disease, relapse, and relapse-free survival

Between February 1972 and December 1987, 192 adults (greater than or equal to 18 years old) with acute lymphoblastic leukemia were transplanted using genotypically HLA-identical marrow donors. Median patient age was 23 years. Eighty-nine patients were in marrow remission and 103 were in relapse. Conditioning regimens included chemotherapy alone (three patients) or in combination with 9.2-17.5 Gy total body irradiation (189 patients). Graft-versus-host disease (GVHD) prophylaxis consisted of methotrexate and/or cyclosporine. Seventy-nine patients developed grades II-IV acute GVHD and 28 of 122 patients who survived at least 100 days developed chronic GVHD. Relapse-free survival at 5 years was 21% for patients transplanted in first remission, 15% for those in greater than or equal to 2nd remission, and 12% for those transplanted in relapse. Patient and donor characteristics were evaluated in multivariate analyses for their effect on development of acute GVHD, survival, relapse, and relapse-free survival. An increased risk of developing acute GVHD was associated with increasing donor age. Variables significantly associated with both increased survival and relapse-free survival included transplantation in first remission, younger patient age, and not developing interstitial pneumonia. A decreased probability of relapse was associated with transplantation in first remission, male patient sex, and grades II-IV acute GVHD.     

Estimating leukemia-free survival after allografting for chronic myeloid leukemia: a new method that takes into account patients who relapse and are restored to complete remission

A significant number of patients who relapse after allogeneic stem cell transplantation (SCT) for chronic myeloid leukemia (CML) will achieve sustained remissions after treatment with interferon-alpha, second transplants, or donor lymphocyte infusions (DLI) from the original stem cell donor. Because leukemia-free survival (LFS) is at present defined as survival without evidence of relapse at any time posttransplant, patients who relapse but are then restored to complete remission are treated as failures when estimating LFS. We have established a new category of LFS, termed current LFS (CLFS), which we define as survival without evidence of leukemia at the time of most recent assessment. To gauge the contribution of treatment for relapse to the efficacy of allogeneic SCT in the management of CML in chronic phase, we compared conventional LFS and CLFS in 189 consecutive patients who underwent SCT over a 7-year period with a minimum follow-up of 3 years. Patients with sibling donors (n = 111) received cyclosporine and methotrexate as prophylaxis for graft versus host disease; patients with unrelated donors (n = 78) also received Campath-1G or 1H as intravenous T-cell depletion. The 5-year LFS defined conventionally was 36% (CI: 29% to 43%) versus a 5-year CLFS of 49% (CI: 36% to 62%). This new method of defining LFS confirms the view that appropriate "salvage" therapy, principally DLI, makes a major contribution to the capacity of allogeneic SCT to produce long-term LFS in patients who receive SCT for CML and emphasizes the importance of redefining LFS to take account of successful treatment of relapse.     

Donor T-lymphocyte infusion for unrelated allogeneic bone marrow transplantation with CD3+ T-cell-depleted graft

In T-cell-depleted allogeneic bone marrow transplantation (TCD-BMT) using unrelated donors, the role of donor lymphocyte infusion (DLI) for survival and disease control has not been defined. In a study of 116 patients (92 matched, 24 mismatched) who received CD3+ T-cell-depleted marrow graft, sequential infusions of escalated doses of donor T lymphocytes up to 1 x 10(6) CD3+ cells/kg were prospectively investigated. T cells were administered while patients were on cyclosporine, provided >or=grade II acute graft-versus-host-disease (GVHD) had not occurred. Acute GVHD of >or=grade II occurred in 27 of 110 (25%) patients before DLI and in 39 of 79 (49%) patients after DLI. In total, 12 of 27 (44%) patients without DLI and 44 of 72 (61%) patients who received DLI developed chronic GVHD. A total of 19 patients died of GVHD, with 17 of acute and two of chronic GVHD. Overall survival (OS) and event-free survival (EFS) at 5 years were 27 and 21%, respectively. The 2-year incidence of relapse was 14%. In multivariate analysis, only chronic GVHD was a good prognostic factor for both OS: hazard ratio (HR) 1.4, P=0.04, and EFS: HR 1.6, P=0.01. Both acute and chronic GVHD were favorable prognostic factors for relapse probability: HR 1.9 for both, P=0.02, 0.01, respectively. The 1-year cumulative incidence of transplant-related mortality (TRM), excluding cases of GVHD, was 42%. The two most common causes of 1-year non-GVHD death were viral infection (9%) and idiopathic pneumonia syndrome (12%). Although the incidence of relapse was low, the study suggests that the current scheme of DLI in unrelated TCD-BMT would not improve survival unless TRM decreases significantly.     

Prevention of relapse using granulocyte CSF-primed PBPCs following HLA-mismatched/haploidentical, T-cell-replete hematopoietic SCT in patients with advanced-stage acute leukemia: a retrospective risk-factor analysis

The role of donor lymphocyte infusion (DLI) in the prophylaxis of relapse has not been defined. We retrospectively analyzed the data from 88 patients with advanced-stage acute leukemia after HLA-mismatched/haploidentical hematopoietic SCT (HSCT) whose treatment did (n=61) or did not (n=27) include granulocyte CSF (GCSF)-primed PBPCs infusion (GPBPCI). The two groups were compared with respect to relapse and OS. Further, a detailed analysis of risk factors was performed. The 2-year cumulative incidence of relapse in patients receiving prophylactic GPBPCI and not receiving prophylactic GPBPCI were 36% and 55% (P=0.017), respectively. Estimated survival at 3 years was 31% for patients receiving prophylactic GPBPCI and 11% for patients not receiving prophylactic GPBPCI (P=0.001). The three-year probability of leukemia-free survival was also higher in patients who received prophylactic GPBPCI (22%) compared with patients who did not (11%) (P=0.003). Multivariate analysis for relapse showed that use of prophylactic GPBPCI after transplantation was an independent prognostic factor (P=0.025). Higher OS was associated with use of prophylactic GPBPCI (P=0.002), AML (P=0.027) and female sex (P=0.023). Our results suggest that use of prophylactic GPBPCI may increase survival of patients with advanced-stage acute leukemia who receive HLA-mismatched/haploidentical HSCT.