An unusual extramedullary relapse of acute nonlymphocytic leukemia after allogeneic bone marrow transplantation

Recurrent leukemia following allogeneic bone marrow transplantation (BMT) for acute nonlymphocytic leukemia (ANLL) continues to be a cause of morbidity and mortality. Most relapses occur within the first 6-12 months, although disease-free survival curves do not begin to plateau until 24 months posttransplant. The majority of relapses occur in the bone marrow. Extramedullary relapses usually occur in "sequestered sites," i.e., the testis and central nervous system. Although the true incidence of extramedullary relapse in "nonsequestered" sites after allogeneic BMT for ANLL is unknown, it appears that this type of relapse is distinctly unusual. The authors present a case of an unusual extramedullary relapse of ANLL in the breast at day +613 after allogeneic BMT for ANLL. In addition, we briefly review the English BMT literature and discuss the differential diagnosis of breast masses in women who survive allogeneic BMT for ANLL.     

Combination chemotherapy of intermediate-dose cytarabine, idarubicin, plus etoposide and subsequent mobilized donor leukocyte infusion for relapsed acute leukemia after allogeneic bone marrow transplantation

The efficacy and side effects of intermediate-dose cytarabine, idarubicin plus etoposide and subsequent donor leukocyte infusion (DLI) were investigated in patients with acute leukemia who relapsed after allogeneic bone marrow transplantation (BMT). Patients were given cytarabine continuous i.v. (1 g/m2 per day x 5), idarubicin i.v. (12 mg/m2 per day x 3), and etoposide i.v. infusion (150 mg/m2 per day x 3). Two days later, G-CSF mobilized donor leukocytes were infused for 2 days. No graft-versus-host disease (GVHD) prophylaxis was given. Between August 1997 and February 2000, 13 patients enrolled (eight acute myeloid leukemia (AML) and five acute lymphoblastic leukemia (ALL)). All patients finished chemotherapy and DLI. Eleven patients (85%) achieved complete remission (CR) at median 27 days after DLI. After median follow up of 10.9 months (2.5-33.3), five of 11 patients who achieved CR relapsed. Overall, six of 13 patients were surviving (6/8 AML and 0/5 ALL, P=0.059). Marrow recovery after chemotherapy and DLI was rapid (12 days for absolute neutrophil count (ANC) >500/microl). Side effects included fever with neutropenia (100%), pneumonia (46%), grade II-IV mucositis (69%), grade III-IV acute GVHD (45%), and extensive chronic GVHD (64%). One patient died from chronic GVHD. Chemotherapy containing intermediate-dose cytarabine and DLI produced a high CR rate in acute leukemia in relapse after allogeneic BMT. A fraction of patients are surviving long term. Side effects were substantial but manageable.     

Fibrous dysplasia masquerading as extramedullary relapse after bone marrow transplantation for chronic myeloid leukemia

A 19-year old girl suffered from relapse of chronic myeloid leukemia (CML) after bone marrow transplantation. The disease was controlled by interferon and imatinib mesylate, but was complicated by autoimmune hyperthyroidism. She presented with unilateral proptosis with no extraocular muscle or visual defect at 26 months follow-up. Systemic investigations showed no recurrence of leukemia or thyrotoxicosis. Magnetic resonance imaging revealed an extensive retro-orbital base of skull lesion. A trans-oral biopsy showed fibrous dysplasia and continuous observation was advised. The unusual sequence of events and the differential diagnoses for unilateral proptosis in post bone marrow transplantation (BMT) cases are discussed.     

Multiple bone lesions after allogeneic bone marrow transplantation in a patient with relapsed adult acute lymphoblastic leukemia: minimal residual disease analysis may predict extramedullary relapse

We describe a patient with acute lymphoblastic leukemia (ALL, L2) who relapsed with multiple bone lesions after allogeneic bone marrow transplantation (allo-BMT). Allo-BMT was performed from an HLA-identical sibling during the first hematological complete remission (CR). Minimal residual disease (MRD) assessed by polymerase chain reaction (PCR) with primers for T cell receptor delta (TCRdelta) gene became positive in the bone marrow sample on day 46 after allo-BMT. On day 113, the patient complained of a painful tumor at the right clavicle. The examination of biopsy specimen revealed infiltration of leukemic cells. After partial response was achieved by local radiotherapy, disseminated bone lesions were demonstrated by 99mTC scintigraphy scan, followed by bone marrow relapse on day 137. The patient died of cardiac tamponade on day 236 after Allo-BMT. MRD assessed by PCR assay for TCRdelta gene in the bone marrow is useful for the prediction of extramedullary as well as medullary relapse after BMT.     

Central nervous system relapse after bone marrow transplantation for acute myeloid leukemia

Central nervous system (CNS) relapse with meningeal leukaemia occurred 6 months after allogeneic bone marrow transplantation (BMT) for acute myeloid leukaemia, without systemic relapse. Despite intrathecal chemotherapy a severe progressive proprioceptive impairment of the lower limbs developed. Autopsy revealed selective ascending tract degeneration of the gracile fasciculi of the posterior columns of the spinal cord and residual endoneurial deposits were found in lumbosacral dorsal nerve roots and ganglia. While CNS relapse may occur in acute leukaemia after chemotherapy, it has rarely been reported following BMT.     

Early myelodysplastic syndrome after allogeneic bone marrow transplantation for acute myeloid leukemia

A 19-year-old male with de novo acute myeloid leukemia (AML) in complete remission received a bone marrow transplant from a HLA-matched donor. Because of major incompatibility for ABO blood type, bone marrow mononuclear cells of the donor were infused after conditioning including total body irradiation (TBI). Engraftment was confirmed on day +23. On day +91, recipient ABO blood genotype was detected in burst forming-unit erythroid (BFU-E) using polymerase chain reaction. Thereafter, myelodysplastic syndrome (MDS) of recipient origin rapidly developed and progressed into a chronic myelomonocytic leukemia-like disorder. An association between MDS and TBI is suggested.     

Induction of graft-versus-leukemia to prevent relapse after partially lymphocyte-depleted allogeneic bone marrow transplantation by pre-emptive donor leukocyte infusions.

In this prospective study we analyzed pre-emptive donor leukocyte infusions (DLI) in 82 consecutive patients transplanted with partially T cell-depleted grafts for acute myeloid leukemia, acute lymphoid leukemia, chronic myeloid leukemia, refractory anemia with excess of blasts, refractory anemia with excess of blasts in transformation and multiple myeloma. Donors were HLA-identical siblings. Patients without significant acute (>grade 1) and/or chronic GVHD were scheduled to be treated with DLI (35 patients) and 31 actually received DLI. Patients who developed acute GVHD >grade 1 and/or chronic GVHD were not scheduled to receive DLI and served as a comparison group (47 patients). The median interval between BMT and DLI was 22 weeks. The first six patients received 0.7 x 10(8) CD3+ cells/kg body weight (b.w.). Five out of these six patients developed acute GVHD (grade 1: n = 2, grade 3: n = 2 and grade 4: n= 1) which was more frequent and more severe than we had anticipated. In the next 25 patients the number of T lymphocytes was diminished to 0.1 x 10(8) CD3+ cells/kg b.w. which resulted in less frequent and less severe GVHD. Eight patients in this group developed acute GVHD (grade 1: n = 4, grade 2: n = 4) and three patients had limited chronic GVHD. Patients in the DLI group needed more time to establish complete donor chimerism confirmed by a higher number of mixed chimeras at 6 months after BMT. The projected 3-year probability of disease-free survival was 77% for the 35 patients intended to treat with DLI and 45% for the patients of the comparison group (P = 0.024). Relapse rate at 36 months after transplantation was 18% in the patients who were intended to treat with DLI and 44% in the comparison group (P = 0.026). We conclude that pre-emptive DLI is feasible and generates favorable relapse rates in patients who are at high risk for relapse. Furthermore, the incidence and severity of GVHD disease after DLI is dependent on the number of CD3+ cells infused.     

The incidence of recurrence of leukemia in donor cells after allogeneic bone marrow transplantation

A total of 243 patients with acute leukemia received a marrow graft from a donor of the opposite sex. Seventy-five patients subsequently relapsed, and specimens of the recurrent leukemia cells were available for cytogenetic analysis in 54. Three relapses were in donor-type cells. Four patients whose relapses were in host-type cells showed a cytogenic abnormality that differed from the original leukemic clone. We conclude that a ‘new’ leukemia in donor cells, and possibly in host cells, constitutes a small but significant fraction of recurrent leukemia after marrow grafting.     

Salvage chemotherapy with donor lymphocyte infusion and STI 571 in a patient relapsing with B-lymphoblastic phase chronic myeloid leukemia after allogeneic bone marrow transplantation

Relapse is the main cause of treatment failure following hematopoietic stem cell transplantation for blastic phase chronic myeloid leukemia. Treatment options including donor lymphocyte infusion, second transplantation, interferon- and re-induction chemotherapy are often unsuccessful. We report a patient with blastic phase chronic myeloid leukemia relapsing after allogeneic stem cell transplantation. The post-transplant leukemia was characterized with B-lymphoid markers and multiple genetic abnormalities including double Ph-chromosomes. The disease was treated with three courses of salvage chemotherapy combined with donor lymphocyte infusion and bcr-abl tyrosine kinase inhibitor. The leukemia proved to be non-responsive both to immune therapy and STI 571. The presented case demonstrates the need for combination approaches in post-transplant relapsed leukemia and discusses the possible contributing mechanisms of STI-571 resistance.     

Prospective trial of chemotherapy and donor leukocyte infusions for relapse of advanced myeloid malignancies after allogeneic stem-cell transplantation.

PURPOSE: Patients with advanced myeloid malignancies who experience relapse after allogeneic bone marrow transplantation (BMT) have a poor prognosis. Long-term survival after chemotherapy alone, second myeloablative transplant, or donor leukocyte infusions (DLIs) alone is unusual. DLIs may have minimal effectiveness in advanced disease because adequate cellular responses are not able to develop in the presence of bulky, fast-growing disease. A chemotherapy strategy was used to debulk disease before administration of granulocyte colony-stimulating factor (G-CSF)-primed DLIs. PATIENTS AND METHODS: Sixty-five patients experiencing hematologic relapse of myeloid malignancy after HLA-matched sibling BMT were prospectively treated with cytarabine-based chemotherapy, then G-CSF-primed DLIs. No prophylactic immunosuppression was provided. RESULTS: Twenty-seven of 57 assessable patients experienced a complete response. Graft-versus-host disease (GVHD) was observed in 56% of the patients. Treatment-related mortality was 23%. Overall survival at 2 years for the entire cohort was 19%. Patients with a complete response were more likely to survive, with 1- and 2-year survival rates of 51% and 41%, respectively, with a median follow-up of more than 2 years. The 1-year survival for nonresponders was 5%. A posttransplant remission lasting more than 6 months before relapse was associated with a higher likelihood of response. GVHD was not required for durable remission. CONCLUSION: Salvage treatment with chemotherapy before DLI can help some patients with advanced myeloid relapse and is not dependent on GVHD. Patients with short remissions after BMT are unlikely to benefit from this approach, and the approach is associated with significant treatment-related mortality. Modifications of this approach or entirely different approaches will be required for most patients with this difficult clinical problem.     

Unrelated donor leukocyte infusions to treat relapse after unrelated donor bone marrow transplantation

Allogeneic stem cell transplantation (SCT) may cure many patients with hematologic malignancies due to both the intensive conditioning therapy, and in many patients, the potent graft-vs-leukemia (GVL) effect of the donor graft. The GVL effect is mediated in large part by mature T-cells contained in the donor graft and has been defined in detail in animal models of transplantation. The GVL activity has been observed in the clinical setting after SCT from both matched siblings and unrelated donors. The best demonstration and most direct evidence of GVL activity in humans come from the use of donor leukocyte infusions (DLI). For patients who relapse with chronic myelogenous leukemia after matched sibling SCT, infusions of leukocytes collected from the original transplant donor will re-establish complete and durable remission in 60-80% of patients. DLI is less effective for more advanced phases of CML and for patients who relapse with diseases other than CML. DLI after matched sibling SCT is complicated primarily by graft-vs-host disease (GVHD), marrow aplasia, and unfortunately, relapse in some cases. There has been little information regarding the use of unrelated DLI (UDLI). Available data now shows that despite initial concerns that UDLI would result in excessive toxicity, it is an effective approach to relapse after unrelated donor marrow grafting. Response rates are similar to those seen after the use of matched sibling DLI, and many remissions remain durable. Graft-vs-host disease is a frequent complication after UDLI though the incidence and severity of GVHD is also similar to the use of matched sibling DLI. It is not clear that the GVL and GVHD effects can be separated, since the majority of responding patients also develop GVHD. The most effective cell dose for UDLI has not been established, though there does not appear to be either a dose-response or dose-toxicity relationship from UDLI. Although second unrelated donor bone marrow transplantation (BMT) may cure a small minority of patients, GVL induction with UDLI offers a safer and potentially more effective therapy for relapsed leukemia, and offers insights in methods to manipulate the human immune system for therapeutic benefit.     

Filgrastim as an alternative to donor leukocyte infusion for relapse after allogeneic stem-cell transplantation.

PURPOSE: Donor leukocyte infusion (DLI) effectively treats relapse after allogeneic stem-cell transplantation (alloSCT), but the response may require several months and may be associated with significant toxicity. Filgrastim has also been observed to effectively treat leukemic relapse after alloSCT. A retrospective analysis was performed to determine the effectiveness of filgrastim in treating relapses after alloSCT. PATIENTS AND METHODS: Fourteen patients with hematologic malignancies were treated with filgrastim at relapse after alloSCT. Filgrastim was given at 5 mcg/kg/d subcutaneously for 21 consecutive days. Response was evaluated at 7 days after completion of filgrastim. Immunosuppressants, if present, were rapidly tapered to complete discontinuation at the time of relapse. RESULTS: Three patients were not assessable for response because additional therapy was necessary before completion of filgrastim. Six patients (43%) achieved a complete response on an intent-to-treat basis. When response was evaluated based on relapse type, three of four cytogenetic relapses, two of three morphologic relapses, and one of four hematologic relapses achieved a complete remission. Two responses were observed in patients who were completely off of any immunosuppression at the time of relapse. Six patients developed chronic graft-versus-host disease. The event-free and overall survival rates for all 14 patients are 43% and 73%, respectively. CONCLUSION: The use of filgrastim with rapid discontinuation of immunosuppression results in response rates that are similar to results using DLI. Filgrastim could be considered as an alternative or an adjunct to DLI for relapses after alloSCT.     

Extra-medullary relapse of leukemia following allogeneic bone marrow transplantation.

The curative effect of allogeneic bone marrow transplantation (BMT) for acute and chronic leukemia is attributed to the intensive conditioning chemotherapy with or without radiotherapy, as well as an immune-mediated graft versus leukemia (GVL) effect. A different pattern of relapse has been observed after allogeneic BMT for patients with leukemia. Compared with treatment using conventional chemotherapy alone, isolated extra-medullary relapse of disease appears to be seen more commonly after allogeneic BMT. While a full donor's hematopoiesis may be retained, prolonged morphological remission has been observed in the recipient's bone marrow. There appears to be a population of leukemic cells with an affinity to extra-medullary tissues. The failure of the leukemic clone to repopulate the recipient's marrow suggests the presence of a more profound GVL effect in the marrow environment. The optimal treatment for extra-medullary relapse of leukemia following allogeneic BMT remains uncertain. In the case of isolated extra-medullary relapses following BMT, the leukemia may still be responsive to further treatment with chemotherapy and/or radiotherapy. The prognosis is poor in general, but prolonged survival has been observed in some of these patients. With the preservation of donor's hematopoiesis in the recipient's marrow, the use of intensive chemotherapy followed by donor lymphocyte or stem cell re-infusion is a promising option.     

Lymphocyte recovery after allogeneic bone marrow transplantation predicts risk of relapse in acute lymphoblastic leukemia.

Allogeneic blood and marrow transplantation (BMT) is curative for many patients with high-risk and relapsed acute lymphoblastic leukemia (ALL). However, relapse is an important cause of post-transplantation failure, and there are no reliable markers to predict relapse. A retrospective review of patients with ALL who underwent matched related allogeneic BMT was carried out to examine whether the rate of lymphocyte recovery after transplantation had any prognostic value in ALL. The absolute lymphocyte count (ALC) at days 21 and 30 after transplantation was obtained for 43 patients who received transplants during an 18-year period. Patients with an ALC of 175 x 10(6)/l or less on day 21 were more likely to relapse than those with ALC greater than 175 x 10(6)/l (relative risk, 4; 95% confidence interval, 1.5-11.2). Patients with slower lymphocyte recovery had significantly lower relapse-free survival than those with faster recovery (P=0.0028). There was also a trend toward poorer overall survival among those with a slow lymphocyte recovery (log-rank test; P=0.028). The rate of lymphocyte recovery is prognostic in patients with ALL undergoing allogeneic BMT, and this should be integrated with other predictors to identify patients at high risk of relapse. Such patients could be considered for interventions aimed at prevention of relapse, including rapid withdrawal of immunosuppressive medication or donor lymphocyte infusion.     

Extramedullary relapse of acute lymphoblastic leukemia in the breast after unrelated allogeneic bone marrow transplantation

A 28-year-old female presented with an isolated extramedullary relapse in the breast following an unrelated allogeneic bone marrow transplantation(UBMT)for acute lymphoblastic leukemia. She complained of a tumor in her right breast with hematological complete remission 23 months after her first UBMT. The extramedullary lesion resolved with chemotherapy, and she then received a second UBMT. Although there had been no relapse of leukemia in the bone marrow and extramedullary sites, she died from a herpes simplex virus infection in the central nervous system. Extramedullary relapses in the so-called 'sanctuary'sites after hematopoietic stem cell transplantation are unusual, and breast recurrences are even more rare. A treatment strategy for unusual sites of relapse after BMT should be established.     

Early detection of relapse by hypermetaphase fluorescence in situ hybridization after allogeneic bone marrow transplantation for chronic myeloid leukemia.

PURPOSE: Standard G-band cytogenetic analysis (CG) provides information on approximately 25 metaphases for monitoring the presence of Philadelphia chromosome positive (Ph+) cells in chronic myelogenous leukemia (CML) patients, making the detection of a low frequency of Ph+ cells problematic. The purpose of this study was to improve the detection of a low frequency of Ph+ cells. PATIENTS AND METHODS: We combined fluorescence in situ hybridization (FISH) with long-term colcemid exposure, capturing several hundred metaphases in bone marrow cultures (hypermetaphase FISH [HMF]). Using probes that identify Ph+ cells, HMF was compared with CG analysis in the follow-up evaluations of 51 patients with CML at various time points after allogeneic bone marrow transplant (BMT). RESULTS: Thirty-five patients never showed the presence of Ph+ cells by either method. In four patients, high frequencies of Ph+ cells were detected by both methods. In the remaining 12 patients, Ph+ cells were detected by HMF at time points after BMT when they were not detected by CG. In seven of the 12 patients, low but statistically significant frequencies of Ph+ cells (0.37% to 5.20%) were detected 3 months or later after BMT, and when no intervention was initiated, all seven patients later relapsed. Based on those data, an eighth patient with mixed chimerism and a similar HMF-detected Ph+ frequency (1.8% at 27 months after BMT) was reinfused with donor lymphocytes and achieved remission with 0% Ph+ cells studied by HMF (up to 50 months after BMT). Ph+ cells detected by HMF but not by CG less than 3 months after BMT disappeared on later examination in two of four patients. After detection of Ph+ cells by HMF only, the median time to cytogenetic progression (detection of Ph+ cells by CG) was 101 days. CONCLUSION: The results demonstrate the ability of HMF to detect low but clinically relevant levels of leukemic cells not detected by CG in transplant patients. The data indicate that HMF can detect low levels of Ph+ cells before standard cytogenetics at a time that may be useful in monitoring disease status and planning clinical interventions.     

单倍型供者淋巴细胞输注治疗复发性急性白血病

Objective To evaluate the effect of haploidentical lymphocyte infusion on refractory and relapse acute leukemia. Methods The haploidentical donor lymphocyte infusion was used to treat for relapse acute myeloid leukemia 3 patients (M2 2 eases, M4 lcase), one relapse acute lymphocyte leukemia from April 2006 to October 2007. Four cases who had accepted secondly regimens were ineffective,after relapse. Collecting donor lymphocytes, parents children as donor supply in 3 cases, mother as donor supply one case. Before donor lymphocyte infusion patients received chemotherapy of different regimens. Donor haploidentical iymphocytes irradiated by 6-8 Gy radial were infused when patients white cell count was at the lowest after the chemotherapy. The average of infusion cells was 2.3 (1.4-3.1)×108/kg. Results One patient acquired complete remission and two patients were effective in three relapse acute myeloid leukemia. It was ineffective in relapse acute lymphocyte leukemia. No transfusion related graft versus host disease was observed. One patient has had herpes zoster virus infection. Conclusion Haploidentical donor lymphocyte infusion with chemotherapy are effective for refractory and relapse in acute myeloid leukemia, but the infused cell quantity and irradiated dosage must be further discussed.     

单倍型供者淋巴细胞输注治疗复发性急性白血病

 目的　探讨难治性复发性急性白血病单倍型淋巴细胞输注的疗效。方法　2006年4月至2007年10月应用单倍型淋巴细胞输注治疗复发性急性髓性白血病（AML）3例（M2 2 例,M4 1例）,复发性急性淋巴细胞白血病（ALL）1例,4例复发患者在二线方案化疗无效后,采集供者淋巴细胞,子女供父母3例,母供子1例,供者淋巴细胞在输注前,患者再次接受了不同方案的化疗,白细胞较低时输注供者的淋巴细胞,平均输注细胞2.3（1.4～3.1）×108／kg,输注前淋巴细胞接受了6～8 Gy 60Coγ射线照射。结果　3例AML患者1例获得了完全缓解（CR）,2例有效,1例ALL无效。4例患者输注单倍型供者淋巴细胞后无移植物抗宿主病的发生,未出现严重的骨髓抑制,1例患者发生了带状疱疹病毒感染。结论　单倍型供者淋巴细胞输注配合化疗对难治复发的AML有疗效,输注细胞的数量及照射的剂量需进一步探讨。     

单倍型供者淋巴细胞输注治疗复发性急性白血病

Objective To evaluate the effect of haploidentical lymphocyte infusion on refractory and relapse acute leukemia. Methods The haploidentical donor lymphocyte infusion was used to treat for relapse acute myeloid leukemia 3 patients (M2 2 eases, M4 lcase), one relapse acute lymphocyte leukemia from April 2006 to October 2007. Four cases who had accepted secondly regimens were ineffective,after relapse. Collecting donor lymphocytes, parents children as donor supply in 3 cases, mother as donor supply one case. Before donor lymphocyte infusion patients received chemotherapy of different regimens. Donor haploidentical iymphocytes irradiated by 6-8 Gy radial were infused when patients white cell count was at the lowest after the chemotherapy. The average of infusion cells was 2.3 (1.4-3.1)×108/kg. Results One patient acquired complete remission and two patients were effective in three relapse acute myeloid leukemia. It was ineffective in relapse acute lymphocyte leukemia. No transfusion related graft versus host disease was observed. One patient has had herpes zoster virus infection. Conclusion Haploidentical donor lymphocyte infusion with chemotherapy are effective for refractory and relapse in acute myeloid leukemia, but the infused cell quantity and irradiated dosage must be further discussed.