Previous Autologous Stem Cell Transplantation Research Articles

Nonmyeloablative Stem Cell Transplantation Is an Effective Therapy for Refractory or Relapsed Hodgkin Lymphoma: Results of a Spanish Prospective Cooperative Protocol

We report the results of reduced-intensity conditioning allogeneic stem cell transplantation (allo-RIC) in patients with advanced Hodgkin lymphoma (HL). Forty patients with relapsed or refractory HL were homogeneously treated with an RIC protocol (fludarabine 150 mg/m 2 intravenously plus melphalan 140 mg/m 2 intravenously) and cyclosporin A and methotrexate as graft-versus-host disease (GVHD) prophylaxis. Twenty-one patients (53%) had received >2 lines of chemotherapy, 23 patients (58%) had received radiotherapy, and 29 patients (73%) had experienced treatment failure with a previous autologous stem cell transplantation. Twenty patients (50%) were allografted in resistant relapse, and 38 patients received hematopoietic cells from an HLA-identical sibling. Five patients (12%) died from early transplant-related mortality (before day +100 after allo-RIC). One-year transplant-related mortality was 25%. Acute GVHD developed in 18 patients (45%). Chronic GVHD developed in 17 (45%) of the 31 evaluable patients. The response rate 3 months after the allo-RIC was 67% (21 [52%] complete remissions and 6 [15%] partial remissions). Eleven patients received donor lymphocyte infusions (DLIs) for disease relapse. The response rate after DLI was 54% (3 complete remissions and 3 partial remissions). Overall survival (OS) and progression-free survival (PFS) were 48% ± 10% and 32% ± 10% at 2 years, respectively. Refractoriness to chemotherapy was the only adverse prognostic factor for both OS (63% ± 12% versus 35% ± 13%; P = .05) and PFS (55% ± 16% versus 10% ± 9%; P = .006). For patients with failure of a prior autologous hematopoietic stem cell transplantation, results were especially good for those who experienced late relapses (≥12 months: 2-year OS and PFS were 75% ± 16% and 70% ± 18%, respectively). These data suggest that allo-RIC is feasible in heavily pretreated HL patients and has an acceptable early transplant-related mortality. Results are better in patients allografted in sensitive disease. Both responses observed after the development of GVHD and DLI may suggest a graft-versus-HL effect. Allo-RIC has to be considered an effective therapeutic approach for patients who have had treatment failure with a previous autologous hematopoietic stem cell transplantation.

Reduced-Intensity Conditioning (RIC) Followed by Allogeneic Stem Cell Transplantation (SCT) for Relapsed Lymphomas: Impact of Pre-Transplantation Factors on Long-Term Outcome.

Allogeneic stem cell transplantation (SCT) represents a potentially curative treatment for recurrent lymphoid malignancies. In fact, potential advantages include the use of a tumor free graft and immune-mediated graft-versus-lymphoma effect. Here, we analyzed the impact of pre-transplantation factors on outcome in 141 lymphoma patients (pts) receiving RIC and allogeneic SCT from HLA-identical sibling donors. Histologic types included in the study were: low-grade non-Hodgkin lymphoma (LG-NHL; n=58), high-grade NHL (HG-NHL, n=55), Hodgkin disease (HD; n= 28). Median age was 50 years (range: 20–69). The three groups (HD vs LG-NHL vs HG-NHL) had similar characteristics in terms of: chemosensitive disease (57% vs 69% vs 67%, p=ns) and complete remission (CR) at transplant (18% vs 27% vs 34%, p=ns). Pts with HD had received more lines of chemotherapy (>2 vs ≤2) as compared to LG-NHL and HG-NHL (82% vs 52% vs 42%). Furthermore, the proportion of pts receving previous autologous SCT was significantly higher in HD and HG-NHL versus LG-NHL (75% vs 54% vs 27%). In addition, patients with HG-NHL and HD underwent frequently allo-SCT less than 2 years after diagnosis as compared to LG-NHL (58% vs 39% vs 24%). All patients received debulkying chemotherapy followed by the same RIC containing thiotepa (10 mg/kg), fludarabine (60 mg/ms) and cyclophosphamide (60 mg/kg). GVHD prophylaxis consisted of cyclosporine A and short-course methotrexate. At a median follow-up of 30 months (8–70), the overall survival (OS) and progression-free survival (PFS) were 65% (95%CI, 56–74%) and 57% (95%CI, 47%–67%), respectively. Univariate analysis showed that age (< or > 55 years), donor sex, interval between diagnosis and SCT, number of previous treatments did not influence outcome whereas diagnosis of HD was associated with a significant inferior PFS and OS. Chemosensitive disease (CR+PR) influenced PFS in HG-NHL (p<0.0003) and HD (p<0.0036) but not in LG-NHL (p=0.69). Complete remission at transplant was associated to a significant better PFS in HD (p<0.01) but not in HG-NHL (p= 0.14) and LG-NHL (p=0.7). Previous autologous SCT was associated to inferior PFS (64% vs 50%, p<0.04) but did not affected OS and TRM. By multivariate analysis, diagnosis of HD and refractory disease were associated to an inferior PFS (p<0.0001, p<0.001) whereas diagnosis of HD and no-CR at transplant remained of prognostic value on OS (p<0.006 and p<0.007). We conclude: 1) age and previous treatments, including autologous SCT, are no longer limitations for allogeneic SCT; 2) debulking therapy before RIC allogeneic SCT is required for HD and HG-NHL; 3) new strategies for an early indentification of chemorefractory pts are necessary.

Allogeneic Myelo-Ablative Stem Cell Transplant (SCT) as Salvage Therapy of Reduced-Intensity Conditioned (RIC) SCT: Toxicity and Outcome.

RIC regimens are mainly used for patients who cannot benefit from the myelo-ablative (MA) approach, due to age, previous SCT, or comorbidities, based on an expected early toxicity of MA regimen. Some centers may also choose the RIC strategy in young patients because they have no facilities for the management of prolonged neutropenia. The development of RIC has been so encouraging that programs now compare MA and RIC in patients who could tolerate both approaches. However, RIC may fail, and MA SCT be secondary considered.Objective: The goal of this retrospective survey was to assess the toxicity and outcome of MA after RIC SCT.Patients: 17 patients (14–63 y; 6 CML, 4 AML, 2 CLL, 2 myeloma, 1 NHL, 1 CMML, 1 myelodysplastic syndrome) received a MA SCT after RIC, for relapse (n=12), graft rejection (n=4), or in a planned program (n=1), from an HLA-id sibling (n=12), a familial mismatched donor (n=1), an unrelated donor (n=3) or a cord blood (n=1). The reason for initial RIC approach was age in 4, a research program in 6, comorbidities in 3, and previous autologous SCT in 4 patients. RIC included Fludarabin (Flu)-Busulfan (BU) in 8, Flu-2Gy irradiation in 4, Cyclophosphamide (CPM)-antithymocyte globulin (ATG) in 1, and various Flu- regimens in 4. One patient had 2 consecutive RIC SCTs before MA SCT. The median delay between RIC and MA SCT was 9 months (range: 2.5–36 months). The same donor was used for the 1st and 2nd SCT in 12/17 cases. The MA transplant was conditioned with BU-CY (±VP16) in 9, Cyclo-TBI in 4, and other regimens in 4 patients. The median follow-up after MA SCT was 9 monthsResults: After the MA transplant, 1 patient developed veno-occlusive disease, 2 developed interstitial pneumonia. Five patients died from relapse between 8 and 21 mo after the MA SCT. Seven (41%) died from transplant-related causes at a median of 8 months (GVHD:3; infection:1; multi-organ failure:1; thrombotic microangiopathy:1; EBV proliferative disease:1). 5/17 (29.5%) patients are alive and well 4.5 to 26 months after MA transplant. Three of them have extensive chronic GVHD while they did not develop any GVHD after RIC. The delay between the 2 transplants did not influence the outcome.Conclusion: This survey shows that MA after RIC SCT is feasible, and considering that most of these patients have been initially eligible for RIC because of their age or comorbidities, MA SCT had an acceptable toxicity. It may be considered for patients who relapsed or rejected after RIC transplant.

High-dose melphalan is an effective salvage therapy in acute myeloid leukaemia patients with refractory relapse and relapse after autologous stem cell transplantation

In a pilot study high-dose melphalan (HD-Mel, 200 mg/m2) and autologous stem cell transplantation (ASCT) were administered to 14 patients (median age 52, range 29-60 years) with acute myeloid leukaemia (AML) in first relapse after a previous ASCT in first complete remission (n=11) or chemotherapy (n=3). A first cohort of five patients received HD-Mel as salvage therapy after a previous cycle of mitoxantrone, topotecan and cytarabine (MTC) had failed in four out of five patients, while a second cohort of nine patients received HD-Mel in untreated relapse. Thirteen (93%) of 14 patients achieved a second complete remission (CR2), including all four patients who had been refractory to MTC. No treatment-related mortality was observed after HD-Mel. Thirteen (93%) patients were able to proceed to a dose-reduced allogeneic stem cell transplantation (allo-SCT) from human-leucocyte-antigens-compatible unrelated (n=12) or sibling donors (n=1) in CR2 (n=11) or poor recovery/relapse (n=2) after a median of 2 (1.7-4.5) months following HD-Mel. Three MTC-refractory patients, but none of the upfront HD-Mel patients, died due to an allograft-related non-relapse cause. Nine patients are alive in CR2 after a median of 6 (2-49) months after HD-Mel and a median of 4 (0.6-47) months after a sequential allo-SCT. Although median follow-up is still short, the proportion of patients achieving a CR2, as well as of those proceeding to a subsequent reduced-intensity-conditioning-allo-SCT, is superior to those previously reported. Our results highly encourage to further investigate HD-Mel and ASCT as a promising salvage regimen for relapsed AML patients for whom autologous peripheral blood stem cells are available.

A phase II study of dexamethasone, ifosfamide, cisplatin and etoposide (DICE) as salvage chemotherapy for patients with relapsed and refractory lymphoma

The 4-day combination of dexamethasone, ifosfamide, cisplatin, and etoposide (DICE) is a salvage regimen for lymphoma. We report a prospective phase II multi-center trial of a modified DICE regimen in relapsed or refractory Hodgkin (HL) or non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL), constituting a single day of intravenous administration followed by 3 days of oral administration, aimed at reducing inpatient days without losing efficacy. Forty patients (median age 56, range 25 - 79) were included: 28 (70%) NHL, 9 (23%) HL and 3 (8%) CLL. Fifty-three per cent had received ⩾̸ 2 prior treatment regimens. International Prognostic Index (IPI) was ⩾̸ 2 in 75% of NHL patients. Patients aged ⩾̸ 55 and those with previous autologous stem cell transplantation (ASCT) started on a lower-dose regimen, with dose escalation possible in 2 patients. Overall response rate was 41%. Thirty-eight per cent of patients had stable disease. With a median of 3.1 years of follow-up, estimated progression-free survival (PFS) and overall survival (OS) rates at 3 years were 15% and 43% respectively. OS was longer in the < 55 compared to the ⩾̸ 55 age cohort (P = 0.0091), longer for HL than NHL (P = 0.59 and 0.039 respectively) and longer for Low/Low-Int IPI than High/High-Int IPI (P = 0.0074 and 0.0009 respectively). Median duration of inpatient stay was 3 days. There were no treatment-related deaths. In conclusion, this modification of DICE is an effective and well tolerated salvage regimen, even in this poor prognosis group of patients. Further clinical studies of DICE in first relapse and in older patients, possibly with the addition of rituximab, are warranted.

Reduced-Intensity Conditioning (RIC) Followed by Allogeneic Transplantation in Relapsed Lymphomas: Evidence for Graft-Versus-Lymphoma Effect in Low and High Grade Histologies, but Not in Hodgkin Disease.

Reduced intensity conditioning (RIC) followed by allogeneic stem cell transplantation (SCT) is associated with durable engraftment, low transplant-related mortality (TRM) and clinical remissions in hematologic malignancies. In addition, RIC followed by allograft is feasible also in patients who had failed previous autologous (auto) SCT. Here, we report the outcome of 118 lymphoma pts receiving RIC and allogeneic SCT from HLA-identical sibling donors. Histologic types included in the study were: chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL; n=26), low-grade non-Hodgkin lymphoma (LG-NHL; n=24, 21 follicular NHL), high-grade NHL (HG-NHL, B cell n=28, T cell n=17), Hodgkin disease (HD; n=23). Median age was 50 years (range: 20–69). 47% of pts had refractory disease (46% CLL/SLL; 33% LG-NHL; 44% HG-NHL; 56% HD) and 48% have failed an auto SCT (15% CLL/SLL; 33% LG-NHL; 55% HG-NHL; 82% HD). All pts received debulkying chemotherapy followed by the same RIC regimen with thiotepa (10 mg/kg), fludarabine (60 mg/ms) and cyclophosphamide (60 mg/kg). GVHD prophylaxis consisted of cyclosporine A and short-course methotrexate. All pts engrafted. De-novo acute GVHD developed in 43% of pts and chronic GVHD in 45%. The 2-year TRM rate was 13% and was not influenced by previous auto SCT or hystological type. At a median follow-up of 20 months (range, 6–62 months), 91 pts (77%) are alive (n=69 CR, n=8 PR, n=14 with disease) and 27 died (23%) for disease (n=17) or TRM (n=10). The 2 years PFS rates for CLL/SLL, LG-NHL, HG-NHL, HD were 63%, 78%, 64%, 16%, respectively. Chemorefractory disease at time of SCT was associated with a worse 2-year PFS compared to chemosensitive disease (41% versus 74%, p<0.001). There was a trend toward lower relapse risk for pts developing acute or chronic GVHD (37% versus 50%, p=0.2). The 2-year OS rates for CLL/SLL, LG-NHL, HG-NHL, HD were 77%, 90%, 76%, 56%, respectively. Chemosensitive disease had significant impact on OS (84% 2-year OS compared with 64% for chemorefractory patients; p< 0.007) as well the occurrence of chronic GVHD (87% versus 57%; p<0.0059). Interestingly, previous auto SCT and age > 55 years did not influence OS. Among pts in clinical CR, 24 were suitable for PCR monitoring of residual disease and 17 pts (71%) are in continuous molecular remission. Our study indicates: 1) low TRM in a multicenter phase II study; 2) low risk of relapse and good survival rates in indolent lymphomas; 3) encouraging results in HG-NHL 4) disappointing results in HD

Impact of prophylactic donor leukocyte infusions on mixed chimerism, graft-versus-host disease, and antitumor response in patients with advanced hematologic malignancies treated with nonmyeloablative conditioning and allogeneic bone marrow transplantation

In an attempt to capture graft-versus-tumor effects without graft-versus-host disease (GVHD), the authors initiated a trial of nonmyeloablative allogeneic bone marrow transplantation (BMT) in patients with advanced hematologic malignancies, with the majority of patients having chemotherapy-refractory disease. Forty-two patients received an HLA-matched related donor BMT after a cyclophosphamide and antithymocyte globulin-based conditioning that also included thymic irradiation for patients who had not received prior mediastinal radiotherapy. Prophylactic donor leukocyte infusion (pDLI) at a dose of 1 × 10 7 CD3 + cells per kilogram were given beginning 5 weeks post-BMT to 16 patients with mixed chimerism (MC) but without GVHD, whereas 26 patients did not receive pDLI, either because of GVHD or early relapse. Twelve of 16 patients (75%) receiving pDLI had T cell chimerism at the time of pDLI ≥40%. These patients, by day 100 post-BMT, either converted to full donor chimerism (FDC) (n = 10) or had an increase in or stable donor chimerism (n = 2) after pDLI. Four of 4 patients whose T cell chimerism was ≤20% at the time of pDLI, lost the graft. In contrast, only 5 of 18 evaluable patients (28%) not receiving a pDLI converted to FDC by day 100 post-BMT, 7 maintained MC, and 10 of an evaluable 22 lost the graft. Patients who had undergone a previous autologous stem cell transplant had a higher rate of conversion to FDC (69% v 31%) and higher incidence of GVHD (69% v 34%) compared with those who did not have a previous autologous SCT. Eleven of 16 patients (69%) who received a pDLI achieved a remission with 50% 1-year progression-free survival rate and 44% 3-year overall survival rate. Nineteen of 42 patients (45%) had ≥grade II acute GVHD, including 12 after BMT and 7 after pDLI. Approximately one third of patients, after having initial MC, eventually lost their donor graft. The authors conclude that (1) pDLI has the potential to convert MC to FDC; (2) sustained remissions can be achieved in patients with chemorefractory hematologic malignancies who receive a pDLI, albeit with a significant risk of acute GVHD; and (3) the degree of donor T cell chimerism at the time of pDLI is predictive of the fate of MC, ie, donor T cell chimerism ≥40% or ≤20% at the time of pDLI correlates with conversion of MC or loss of the graft, respectively.

Role of nonmyeloablative allogeneic stem-cell transplantation after failure of autologous transplantation in patients with lymphoproliferative malignancies.

Conventional allogeneic stem-cell transplantation (SCT) after a prior failed autograft is associated with a transplant-related mortality rate of 50% to 80%. The aim of the current study was to evaluate the safety and efficacy of sibling, HLA-matched, nonmyeloablative allogeneic SCT with donor lymphocyte infusion (DLI) in patients with lymphoid malignancy after failure of autologous SCT. A total of 38 patients with refractory, progressive, or relapsed disease after autologous SCT were entered onto this study. The conditioning regimen consisted of the humanized monoclonal antibody CAMPATH-1H, fludarabine, and melphalan. Fifteen of 35 assessable patients received DLI after SCT. Sustained neutrophil engraftment was achieved in 37 recipients, and platelet engraftment was achieved in 35 patients. The estimated transplant-related mortality was 7.9% at day 100 and 20% at 14 months, the median duration of follow-up. Eight patients experienced grade I/II acute graft-versus-host disease (GVHD) after transplantation, but no grade III/IV GVHD was observed in this setting. However, grade III/IV GVHD occurred in seven patients who received DLI. The actuarial overall survival at 14 months was 53%, with a progression-free survival of 50%. DLI produced a further response in three of 15 recipients. Nonmyeloablative allogeneic SCT after CAMPATH-1H-containing conditioning is a relatively safe option compared with conventional allogeneic transplantation for patients who have failed previous autologous SCT. The low incidence of early GVHD enabled the subsequent administration of DLI to improve further clinical responses in this poor-risk group of lymphoma and myeloma patients.