Allogeneic bone marrow transplantation (BMT) for adults with acute lymphoblastic leukemia (ALL): predictive role of minimal residual disease monitoring on relapse

We developed a PCR-based method to monitor clonogenic IgH VDJ rearrangement as a possible predictor of relapse in patients with acute B-ALL after allogeneic bone marrow transplantation (BMT). We studied 23 patients at diagnosis, before and after BMT. At the time of BMT, 13 patients were in first complete remission, eight in second complete remission and two in relapse. Four patients were PCR negative before BMT and remained PCR negative also after BMT (-/- pattern). They are still in remission after a median follow-up of 41 months. Nineteen patients were MRD-positive before BMT: three were PCR negative at first determination after BMT (+/- pattern) and maintain remission. Sixteen patients were PCR-positive at first determination after BMT (+/+ pattern): five became PCR negative (+/+/- pattern) (four with chronic graft-versus-host disease (GVHD) and two after donor lymphocyte infusions (DLI)). Nine patients remained PCR-positive (+/+/+ pattern) (four remain in remission, and six relapsed); two patients died before transplant. In conclusion, PCR negative patients before BMT remained negative post-BMT; many pre-BMT positive patients had initial MRD positivity after BMT: 37% of them achieved a molecular remission with cGVHD or DLI.     

Outcome of allogeneic transplantation in newly diagnosed and relapsed/refractory multiple myeloma: long‐term follow‐up in a single institution

Allogeneic stem cell transplantation (allo‐SCT) has the potential to induce long‐term remission in multiple myeloma (MM), but the role of allo‐SCT in MM is controversial due to the high rate of treatment‐related mortality (TRM). However, although proteasome inhibitors and immunomodulatory drugs have improved the outcome of patients with MM, high‐risk patients still have a very poor prognosis. This indicates the need for new treatment strategies and identification of patients who might benefit from allo‐SCT. We therefore analyzed the outcome of one hundred and forty‐seven patients with MM who received an allo‐SCT at our institution (58 in first line, 89 in relapsed/refractory setting) after a median follow‐up of 88.8 months. For the first‐line setting, median progression‐free survival (PFS) and overall survival (OS) were remarkably good, with a CR rate of 48.3%, median PFS of 30.2 months, and 10‐yr OS of 51%. We found no difference in outcome for patients with high‐risk metaphase cytogenetics or FISH del(13q14), but efficacy in current standard high‐risk patients could not be determined. The outcome in the relapsed/refractory setting was poor, especially in the subgroup of patients relapsing within 18 months after auto‐SCT. Therefore, if applied at all in these patients, improvement of allo‐SCT is needed, focusing on reduction of TRM and more effective immunotherapy.     

Polymerase chain reaction-based detection of minimal residual disease in multiple myeloma patients receiving allogeneic stem cell transplantation

BACKGROUND AND OBJECTIVES: Recent advances in the treatment of multiple myeloma (MM) include use of high-dose chemoradiotherapy followed by allografting. Although allografting with bone marrow (BM) or peripheral blood stem cells (PBSC) seems to improve clinical outcome and lengthen survival, only about 50% of patients reach stringently defined complete remission (CR), and most subsequently relapse. We assessed the clinical relevance of minimal residual disease (MRD) in 14 MM patients in CR after allografting with PBSC (6 patients) or BM (8 patients). DESIGN AND METHODS: Among the 30 out of 72 MM patients in our Institute who achieved CR after allografting, 14 had a molecular marker suitable for allo-specific polymerase chain reaction (PCR) analysis.Stringent molecular monitoring was done using clonal markers based upon rearranged immunoglobulin heavy-chain genes. Molecular remission (MCR) was defined as two consecutive negative PCR results. RESULTS: Seven of 14 (50%) molecularly monitored patients, achieved MCR and did not relapse after a median molecular follow-up of 60 months (range 36-120). Median time to obtain first PCR negativity was 12 (BM group) and 6 months (PBSC group), respectively. Of the seven patients (50%) who never achieved MCR, one relapsed. INTERPRETATION AND CONCLUSIONS: In conclusion, 50% of the MM patients in CR studied by us also achieved stringently-defined MCR. MCR was associated with a very low rate of clinical relapse.     

Relapse risk and survival in patients with FLT3 mutated acute myeloid leukemia undergoing stem cell transplantation

In patients with AML with FMS‐like tyrosine kinase 3 (FLT3) mutations, the significance of minimal residual disease (MRD) detected by PCR before allogeneic stem cell transplantation (SCT) on outcomes after transplant remains unclear. We identified 200 patients with FLT3‐AML who underwent SCT at our institution. Disease status at transplant was: first or second complete remission (CR1/CR2, n = 119), high‐risk CR (third or subsequent CR, marrow hypoplasia, or incomplete count recovery) (CR‐HR, n = 31), and morphological evidence of active disease (AD, n = 50). The median follow‐up was 27 months, and the 2‐year overall and progression‐free survival were 43% and 41%, respectively. Relapse was highest in the AD group (85%) and the CR‐HR FLT3 MRD positive group (72%), followed by CR‐HR FLT3 MRD negative (58%), CR1/CR2 FLT3 MRD positive (39%), and lowest in the CR1/CR2 FLT3 MRD negative group (23%). On multivariate analysis, independent factors influencing the risk of relapse were detectable morphological disease and FLT3 MRD by PCR pre‐transplant. Factors that did not influence the relapse risk included: age, graft type, graft source, type of FLT3 mutation, or conditioning intensity. Morphologic and molecular remission status at the time of transplant were key predictors of disease relapse and survival in patients with FLT3‐AML.     

Allogeneic transplantation for multiple myeloma: late relapse may occur as localised lytic lesion/plasmacytoma despite ongoing molecular remission

Allogeneic SCT for myeloma may be curative for young patients, but its role remains controversial because of a reported high TRM in some series. Since 1991, we have performed 25 allografts for myeloma using fully matched sibling donors. Of the 18 evaluable patients, 13 achieved CR at a median time of 2.5 months post-transplant. The five patients who were not in CR when assessed at 3 months received a short course of alpha-interferon and four subsequently achieved CR with this approach at a median of 82 days. One patient who failed to respond to IFN went on to achieve CR after four doses of DLI therapy, thus giving an overall CR rate of 72%. Seven patients have relapsed at a median of 4.7 years post-transplant (range 1.38-7.7 years) including two patients who had received IFN therapy. In five of these cases, relapse has been as a localised area of bone disease or isolated plasmacytoma with no evidence of marrow involvement by trephine biopsy or molecular analysis. All patients with localised relapse were treated with local radiotherapy +/-DLI and four are currently disease free despite two patients having had further treatment for a second localised lesion. Six patients died of TRM (24%) and the OS at 8 years is currently 69% with an EFS of 26%. These results suggest that allogeneic SCT for myeloma can be carried out with an acceptable TRM and a high CR rate. However, late relapses as localised disease may be a frequent finding and may represent foci of myeloma not eradicated by the conditioning. The use of pretransplant MRI scanning and top-up radiotherapy to involved areas may be useful in preventing this type of relapse.     

Results of risk‐adapted therapy in acute myeloid leukaemia. A long‐term population‐based follow‐up study

In 1997–2003, a protocol for treatment of acute myeloid leukaemia (AML) (except promyelocytic leukaemia) was activated in four Swedish health care regions covering 50% of the national population. Based on cytogenetics and clinical findings, patients aged 18–60 yr were assigned to one of three risk groups. In this report we account for the long‐term clinical outcome of enrolled patients. Patients received idarubicin and cytarabine in standard doses as induction therapy and consolidation courses included high‐dose cytarabine. Allogeneic stem cell transplantation (allo‐SCT) from an human leucocyte antigen‐identical sibling was recommended in standard and poor‐risk patients, whereas unrelated donor transplant was reserved for poor‐risk patients. Autologous (auto‐SCT) was optional for standard or poor risk patients not eligible for allo‐SCT. Two hundred seventy‐nine patients with de novo or secondary (9%) AML, median age 51 (18–60) yr, corresponding to 77% of all patients in the population, were included. Twenty (7%) patients were assigned to the good risk group, whereas 150 (54%) and 109 patients (39%) were assigned to standard‐ and poor‐risk groups, respectively. Induction failures accounted for 55 patients; 16 early deaths eight of whom had white blood cell (WBC) >100 at diagnosis, and 39 refractory disease. Thus, complete remission (CR) rate was 80%. At study closure, the median follow‐up time of living patients was 90 months. Median survival time from diagnosis in the whole group was 27 months and 4‐yr overall survival (OS) rate was 44%. In good, standard, and poor risk groups, 4‐yr OS rates were 60, 57 and 24%, respectively. Median relapse‐free survival (RFS) time in CR1 was 25 months and RFS at 4 yr was 44%. Four‐year RFS rates were significantly (P < 0.001) different between the three risk groups; 64% in good risk, 51% in standard risk and 27% in poor risk patients. One hundred‐ten transplantations were performed in CR1; 74 allo‐SCT (50 sibling, 24 unrelated donor), and 36 auto‐SCT. Non‐relapse mortality was 16% for allo‐SCT patients. Outcome after relapse was poor with median time to death 163 d and 4‐yr survival rate 17%. Three conclusions were: (i) these data reflect treatment results in a minimally selected population‐based cohort of adult AML patients <60 yr old; (ii) a risk‐adapted therapy aiming at early allogeneic SCT in patients with a high risk of relapse is hampered by induction deaths, refractory disease, and early relapses; and (iii) high WBC count at diagnosis is confirmed as a strong risk factor for early death but not for relapse.     

Improved outcome after relapse in children with acute myeloid leukaemia

In the Nordic Society for Paediatric Haematology and Oncology paediatric study acute myeloid leukaemia (AML) 93, event-free survival was 50% and overall survival was 66%, indicating that many patients were cured following relapse. Factors influencing outcome in children with relapsed AML were investigated. The study included all 146 children in the Nordic countries diagnosed with AML between 1988 and 2003, who relapsed. Data on disease characteristics and relapse treatment were related to outcome. Sixty-six percentage achieved remission with survival after relapse (5 years) 34 +/- 4%. Of 122 patients who received re-induction therapy, 77% entered remission with 40 +/- 5% survival. Remission rates were similar for different re-induction regimens but fludarabine, cytarabine, granulocyte colony-stimulating factor-based therapy had low treatment-related mortality. Prognostic factors for survival were duration of first complete remission (CR1) and stem cell transplantation (SCT) in CR1. In early relapse (<1 year in CR1), survival was 21 +/- 5% compared with 48 +/- 6% in late relapse. For children receiving re-induction therapy, survival in early relapse was 29 +/- 6% and 51 +/- 6% in late. Patients treated in CR1 with SCT, autologous SCT or chemotherapy had a survival of 18 +/- 9, 5 +/- 5 and 41 +/- 5%, respectively. Survival was 62 +/- 6% in 64 children given SCT as part of their relapse therapy. A significant proportion of children with relapsed AML can be cured, even those with early relapse. Children who receive re-induction therapy, enter remission and proceed to SCT can achieve a cure rate of 60%.     

Molecular and clinical follow-up after stem cell transplantation for multiple myeloma

 Molecular follow-up has been carried out using immunoglobulin heavy-chain (IgH) gene fingerprinting, a polymerase chain reaction (PCR)-based technique with a sensitivity of 0.1–0.01% (10^–3–10^–4), in 22 patients affected by multiple myeloma and submitted to stem cell transplantation (SCT). Twelve patients were submitted to either single or double autologous unselected peripheral blood progenitor cell transplantation, eight patients were submitted to autologous CD34+ immunoselected transplantation and two patients were submitted to allogeneic bone marrow (one patient) or peripheral blood CD34+ stem cell (one patient) transplantation. At diagnosis, all patients showed clonal CDIII rearrangement. The molecular analysis performed on leukapheresis products and CD34+ purified fractions proved to be contaminated by myeloma cells. During follow-up after autografting, all but one patient retained clonal rearrangement despite clinical complete remission (CR) in ten of them. These ten patients either relapsed (Rel) or showed progressive disease (PD) after transplantation; four of them died. Only one patient did not retain clonal rearrangement after autologous transplantation; she is currently alive in CR after a follow-up of 100 months. One patient submitted to allogeneic transplantation is currently alive with no evidence of the disease, but still retains clonal rearrangement after a follow-up of 47 months. Another patient died 4 months after transplantation after succumbing to fatal pneumonia showing myeloma progression. Received: 28 February 2000 / Accepted: 1 August 2000     

Depth of response assessed by quantitative ASO‐PCR predicts the outcome after stem cell transplantation in multiple myeloma

Achievement of complete response (CR) is a new goal of therapy for multiple myeloma (MM). By sensitive methods, the depth of response can be measured even among the patients in CR. We used a sensitive real‐time quantitative polymerase chain reaction by allele‐specific primers (qASO‐PCR) to assess the level of minimal residual disease (MRD) in bone marrow of 37 patients with myeloma who had achieved CR/near‐to‐CR after autologous or allogeneic stem cell transplantation (SCT). Allele‐specific primers could be successfully designed for 86% of patients. Three to six months after autotransplantation, the PCR target was not detectable in 53% of patients (16/30 patients), and the respective figure after allotransplantation was 71% (5/7 patients); the median sensitivity of PCR assay was <0.002%. The proportion of patients without detectable PCR target was 22% of all autotransplanted patients. A threshold level of 0.01% in the qASO‐PCR assay 3–6 months after SCT was found to be a useful cut‐off limit to divide the patients into two prognostic groups: MRD low/negative vs. MRD high. Low/negative MRD after SCT was a significant predictive factor for the prolongation of progression free (70 vs. 19 months; P = 0.003) and suggestively also for overall survival. We conclude that not only CR but also its depth is important for the long‐term outcome in MM.     

Syngeneic transplantation in multiple myeloma - a case-matched comparison with autologous and allogeneic transplantation. European Group for Blood and Marrow Transplantation.

Twenty-five patients with multiple myeloma received bone marrow grafts (n = 24) or peripheral blood stem cells (n = 1) from twin donors. The outcome was compared in a case-matched analysis to 125 patients who underwent autologous transplantation, and 125 who underwent allogeneic transplantation. Seventeen patients (68%) receiving twin transplants entered complete remission, which was not significantly different from that of autologous (48%) or allogeneic (58%) transplants. The median overall and progression-free survival for the twins was 73 and 72 months, respectively. The overall survival tended to be better (73 vs 44 months) and the progression-free survival was significantly better (72 vs 25 months) than with autologous transplantation and both were significantly better than with allogeneic transplantation. Three of 17 patients who entered complete remission following transplantation had relapsed at follow-up. This relapse rate was significantly lower than following autologous transplantation and similar to the relapse rate with allogeneic transplantation. Only two twins died of transplant-related toxicity. Six further patients died of progressive or relapsing disease. Syngeneic transplantation in multiple myeloma appears to be the treatment of choice if a twin donor is available. A lower relapse risk than in autotransplantation may be due to reinfusion of malignant cells in some patients treated with this modality or to the presence of a graft-versus-myeloma effect in some syngeneic transplants.     

Successful immunotherapy in early relapse of acute myeloid leukemia after nonmyeloablative allogeneic stem cell transplantation

We report on a 35-year-old woman who underwent allogeneic stem cell transplantation (SCT) in second complete remission (CR) of acute myeloid leukemia (AML) after reduced-intensity conditioning with fludarabine and 2 Gy of total body irradiation. For graft-versus-host disease (GVHD) prophylaxis, cyclosporin A (CsA) and mycophenolate mofetil (MMF) were given. On day 27 after SCT complete hematological remission and donor chimerism was documented. However, in CD34(+) bone marrow cells 28% of recipient hematopoiesis persisted. On day +59 leukemic relapse occurred. After discontinuation of CsA and onset of GVHD, complete donor chimerism and hematological CR were achieved which has been maintained for 14 months.     

Bone marrow transplantation for adult poor prognosis lymphoblastic lymphoma in first complete remission

Twenty-five adult patients, 19 males, six females, age 16-43 years (median 23), with lymphoblastic lymphoma received allogeneic or autologous bone marrow transplantation in first complete remission. Twelve patients were Murphy stage IV with bone marrow and/or CNS involvement and 13 were stage III of whom nine had thoracic involvement. Complete remission was achieved with an intensive anthracycline containing multiagent chemotherapy protocol. Twelve patients with an HLA identical sibling received an allogeneic marrow and 13 without a donor received their own marrow harvested a median of 2 months (0-4 months) after complete remission and purged in vitro with either mafosfamide (eight patients) or anti T-cell monoclonal antibodies and complement (three patients). Bone marrow transplantation was performed 1-7 months (median 3 months) after achieving first complete remission. The conditioning regimen consisted of cyclophosphamide or high dose melphalan and total body irradiation. The actuarial 4-year disease-free survival is 68% (+/- 9% SE). The actuarial probability of relapse was 26% (+/- 3% SE) with a median follow up to 22 months. There was no difference between allogeneic and autologous transplantation with eight out of 12 allo patients in first continuous complete remission 26-45 months after transplant and nine out of 13 auto in continuous complete remission 15-75 months after transplant. These results compare favourably with those achieved with the best chemotherapeutic regimen used for such patients.     

Rituximab reduces relapse risk after allogeneic and autologous stem cell transplantation in patients with high-risk aggressive non-Hodgkin's lymphoma

High-dose chemotherapy and autologous stem cell transplantation (SCT) have limited success in patients with refractory aggressive lymphoma. Allogeneic SCT may offer some advantage in this setting by providing graft-versus-lymphoma effect, but the relapse risk remains substantial. In this study, we evaluated the safety and efficacy of rituximab administration after SCT in patients at high-risk for post-transplant relapse, in order to reduce relapse risk. Twenty-eight patients were included with the intent to treat them with rituximab after autologous (n = 16) or allogeneic (n = 12) SCT. Twenty-four were given rituximab starting a median of 47 d post SCT. Three died of SCT complications prior to therapy. Nine patients not achieving a complete remission (CR) post SCT converted to CR with rituximab and with the onset of graft-versus-host disease (GVHD) in three. With a median follow-up of 12 months (range, 3-33 months) the estimated 2-year overall survival and disease-free survival was 85 +/- 7% and 55 +/- 13% respectively. When only those patients who were actually treated are analysed, these rates were 95 +/- 7% and 64 +/- 13% respectively. The relapse risk was 35 +/- 14%. Seven patients had recurrent neutropenia episodes associated with severe hypogammaglobulinaemia, which were further prevented with intravenous immunoglobulin. None of the 10 allogeneic SCT recipients treated with rituximab had severe GVHD. Rituximab may be an effective adjuvant therapy after SCT to reduce the relapse rate and improve the outcome in high-risk aggressive lymphoma. Larger scale comparative trials are necessary to better define its role in SCT.     

Multiple myeloma patients receiving pre-emptive donor lymphocyte infusion after partial T-cell-depleted allogeneic stem cell transplantation show a long progression-free survival

The purpose of this study was to determine the role of pre-emptive donor lymphocyte infusion (pDLI) after partial T-cell-depleted allogeneic SCT in patients with multiple myeloma (MM). A cohort of 24 MM patients was treated with partial T-cell-depleted myeloablative SCT between December 1997 and April 2002. These patients were intended to receive pDLI after SCT. The overall response rate after SCT was 83% (20 of 24 patients) with 10 patients (42%) in complete remission (CR). Transplant-related mortality within 1 year after SCT was 29%. Thirteen patients (54%) received pDLI and four patients in partial remission reached CR. GVHD>grade I after pDLI developed in 4 out of 13 patients (30%). Four patients received therapeutic DLI, without preceding pDLI. Eleven patients (46%) are alive, with a median follow-up of 67 months (range, 48-100 months). Seven of these patients (29%) are in continuous CR (CCR), which was confirmed by a negative patient-specific IgH PCR in four patients. All seven patients in CCR received pDLI. Although myeloablative SCT in MM induces high toxicity, we show that the concept of T-cell depletion followed by pDLI is promising and needs to be investigated in a reduced-intensity conditioning setting.     

High-dose vincristine, fractionated total-body irradiation and cyclophosphamide as conditioning regimen in allogeneic and autologous bone marrow transplantation for childhood acute lymphoblastic leukaemia in second remission: a 7-year Italian multicentre study

We investigated the feasibility and efficacy of high-dose vincristine (4 mg/m² over 4 d) combined with fractionated total body irradiation (F-TBI) (200 cGyx2 over 3 d) and cyclophosphamide (60 mg/kg for 2 d) as a preparative regimen in allogeneic (AlloBMT) and autologous (ABMT) bone marrow transplantation for 75 consecutive children (median age at transplant 8-5 years) with acute lymphoblastic leukaemia in second complete remission (CR). Median duration of first CR was 26 and 25 months in the AlloBMT and ABMT group, respectively. Of the 46 patients who underwent AlloBMT, 33 had isolated or combined marrow relapse and 13 isolated extramedullary relapse. Of the 29 patients given ABMT, 23 had preBMT isolated or combined marrow relapse and six isolated extramedullary relapse. 44/75 patients are alive and in CR at a median follow-up of 35 months (range 10-90 months). Seven children given AlloBMT (15.8%) and two given ABMT (7%) died from transplant-related causes. No major early organ toxicity, including vincristine-related toxicity, was recorded. The overall 3-year EFS estimate (95% CL) was 53.8% (42-66%): in particular, 58.2% (40-76%) for AlloBMT and 27.6% (9-46%) for ABMT patients who experienced a marrow relapse before transplant. The overall 3-year relapse rate estimate (95% CL) was 39.2% (27-51%): in particular, 30.1% (12-49%) in the AlloBMT group and 72% (54-91%) in the ABMT group ( P < 0.01) who presented a preBMT isolated or combined marrow relapse. We conclude that the conditioning regimen with high-dose vincristine combined with cyclophosphamide and F-TBI is feasible and promising, although its therapeutic advantage should be tested in larger series of patients enrolled in randomized studies.     

Hematopoietic stem cell transplantation in the second or later complete remission in acute promyelocytic leukemia initially treated with all-trans retinoic acid

Despite the use of all-trans retinoic acid (ATRA) as the first-line treatment for acute promyelocytic leukemia (APL), relapse occurs in about 20% of cases. Most relapsing APL patients can achieve second remission (CR2) following ATRA combined with chemotherapy or arsenic trioxide. Stem cell transplantation (SCT) has been widely adopted in CR2, but optimal SCT (auto- or allo-SCT) remains controversial. We analyzed the outcomes for 8 APL patients initially treated using ATRA, who relapsed, achieved CR2 and underwent auto-SCT (n = 4) or allo-SCT (n = 4). The mean age of patients who underwent allo-SCT was 39 years. Minimal residual disease (MRD) just prior to SCT was positive in 1 patient and negative in 3. Engraftment was achieved in all patients, but 2 patients died of transplantation-related complications within 6 months. Complete molecular remission has been maintained in the remaining 2 patients. The mean age of patients who underwent auto-SCT was 48 years. MRD just prior to SCT was negative in all 4 patients. Complete molecular remission has been maintained in all 4 patients (mean follow-up, 3 years 9 months). The results for auto-SCT are favorable in patients with MRD-negative APL.     

Outcome after relapse in childhood acute lymphoblastic leukemia

Among 157 children with acute lymphoblastic leukemia (ALL) who experienced relapse at 54 institutes participating in the Japan Association of Childhood Leukemia Study, we analyzed the outcomes after relapse in 103 and 30 eligible cases with bone marrow (BM) and central nervous system (CNS) relapse, respectively. Reinduction rates in BM and CNS relapse cases were 72.3% and 83.3%, respectively. High reinduction rates were observed in B-precursor (B-pre) phenotype ALL in both relapse groups and in late (more than 24 months from onset) BM-relapse patients. After BM relapse, the overall 5-year survival rate was superior in the allogeneic stem cell transplantation (SCT) group compared to the non-SCT group (41.9%+/-8.2% versus 13.6%+/-6.5%, P < .0001). In contrast, the 4-year overall survival rate was not significantly different between the SCT (allogeneic plus autologous) and non-SCT groups after CNS relapse (26.8%+/-14.2% versus 61.9%+/-12.3%, P = .252). The late BM-relapse patients showed a significantly higher survival rate than did early-relapse patients, and survival rates were similar between the allogeneic and autologous group when the patients underwent SCT during a second complete remission. Moreover, B-pre ALL patients classified in the standard-risk group according to National Cancer Institute/Rome's criteria at onset had a good prognosis after allogeneic SCT. Improving the cure rate in relapsed ALL patients requires more intensive reinduction therapy and efforts to succeed with SCT in early BM-relapse patients as well as the establishment of a treatment strategy including indications of SCT for CNS-relapse patients.     

Leukemic relapse in the central nervous system after allogeneic stem cell transplantation with complete remission in the bone marrow and donor-type chimerism: report of two cases

We studied two cases with leukemia that relapsed in the central nervous system (CNS) after allogeneic stem cell transplantation. One patient underwent peripheral blood stem cell transplantation (SCT) from a related, yet haplotype-mismatched, donor for chronic myelomonocytic leukemia. She was kept in complete remission (CR) in the bone marrow (BM) for 7 months, until relapse in the cerebrospinal fluid (CSF) was evident. In the other patient, with acute lymphoblastic leukemia, systemic relapse occurred when he was still on immunosuppression 6 months after SCT from an unrelated donor. After induction chemotherapy following cessation of immunosuppression, the BM examination proved CR. During consolidation chemotherapy, however, he developed leukemic dissemination in the CSF, despite the fact that the BM was in CR. Chimerism status in the BM mononuclear cells and fractionated peripheral blood (PB) cells (granulocytes, T-lymphocytes, and the others) was assessed by short tandem repeat analysis. In both patients, the BM cells and all the fractions of the PB cells proved donor-type chimeras. These results seem to suggest that the graft-versus-leukemia effects might not be as effective in the CNS as in the BM, even when complete T-lymphoid chimerism is achieved.     

Kinetics of plasma-cell chimerism after allogeneic stem cell transplantation by highly sensitive real-time PCR based on sequence polymorphism and its value to quantify minimal residual disease in patients with multiple myeloma

OBJECTIVE: To investigate lineage-specific chimerism of plasma cells after allogeneic transplantation by real-time PCR based on bi-allelic sequence polymorphism or, in case of female-to-male transplantation, on the detection of the DFFRY gene and to determine its value to quantify minimal residual disease in myeloma patients. METHODS: Forty-eight samples from bone marrow samples and peripheral blood from 34 nonmyeloma patients were analyzed at different times after transplantation. Sixty-two samples from 22 myeloma patients were analyzed at different times after allogeneic stem cell transplantation, and results were compared with immunofixation and, in some cases, with PCR data using patient-specific primers. RESULTS: The median chimerism for T cells at day +100 was greater than 99.9% and remained stable on day +180 and 1 year after transplantation. In contrast, the median donor plasma cell chimerism at day +100 was 95.5%, at day +180 98.6%, at day +360 99.8%, and 2 or more years after transplantation greater than 99.9%. Sensitivity of real-time PCR using human short insertion/deletion polymorphisms (SIDP) was 10(-4) and in case of Y-PCR 10(-5). Sequential monitoring of donor plasma cell chimerism showed that increasing and stable chimerism were associated with ongoing remission in 15 out of 16 samples (93%), and decreases in chimerism predicted relapse in 5 out of 6 patients. CONCLUSION: We conclude that plasma cell chimerism after allogeneic stem cell transplantation is delayed in comparison to T-cell chimerism. Sequential quantitative measurement of plasma cells after allogeneic stem cell transplantation with highly sensitive real-time PCR allows monitoring of residual host-tumor cells in patients with multiple myeloma and allows guiding adoptive immunotherapy strategies to enhance remission status and to prevent clinical relapse.