Successful treatment with reduced-intensity cord blood transplantation for acute myeloid leukemia with complete tetraploidy (92, XXXX)

A 56-year-old female was diagnosed with acute myeloid leukemia (FAB: AML-M1). G-banding karyotype of her bone marrow showed complete tetraploidy (92, XXXX [24/24]). Although she achieved complete remission (CR) after induction therapy and maintained CR during consolidation therapy, relapse occurred only 2 months after discharge. When the relapse occurred, bone marrow karyotypic analysis showed complete tetraploidy again. The patient received reduced-intensity cord blood transplantation (RI-CBT), which induced CR for the second time. The patient is currently alive 24 months after transplantation and there have not been any signs of recurrence to date. There have been a few reports of AML with near-tetraploidy, but cases of AML with complete tetraploidy are extremely rare. Tetraploid AML has been reported to have a poor prognosis and there have been very few cases maintaining CR over the long term after chemotherapy alone. This is the first case of complete tetraploid AML successfully treated by RI-CBT. The clinical course of this case suggests that hematopoietic stem cell transplantation during the first CR phase should be considered a treatment option for tetraploid AML.     

Successful Cytoreduction with CAG (cytarabine,Aclarubicin and G-CSF) Therapy in Refractory Acute Myelogenous Leukemia before Allogeneic Stem Cell Transplantation

Refractory acute myelogenous leukemia (AML) has a poor prognosis, and a long-term survival cannot be expected in most patients even if allogeneic bone marrow transplantation (allo-BMT) or allogeneic peripheral blood stem cell transplantation (allo-PBSCT) is performed. An abundance of residual leukemic cells and poor performance status of patients before allo-BMT are often associated with a high relapse rate and high transplant-related mortality. Thus, to improve the prognosis of patients with refractory AML undergoing allo-BMT, it is necessary to reduce the leukemic cell volume as low as possible without severe complications. In this report, we used CAG (cytarabine, aclarubicin and granulocyte colony-stimulating factor (G-CSF)) therapy for cytoreduction before allo-BMT or allo-PBSCT in five patients with refractory AML. One of them achieved complete remission (CR) by CAG therapy alone and others achieved major tumor reduction prior to BMT and PBSCT. All patients achieved CR after allo-BMT and allo-PBSCT without severe complications. Three of them have remained CR for 9, 21 and 30 months, respectively. Although the results of this feasibility study are preliminary, the pre-transplant CAG therapy for refractory AML deserves further evaluation.     

Three AML patients with existing or pre-existing intracerebral granulocytic sarcomas who were successfully treated with allogeneic bone marrow transplantations

We report three acute myelogenous leukemia (AML) patients who developed intracerebral granulocytic sarcomas (GS) and were successfully treated with allogeneic BMT (allo-BMT). The diagnosis of one patient was AML M2 with myelofibrosis, and the other two patients were AML M4 with eosinophilia (AML M4 Eo), according to the FAB classification. Two patients first experienced a relapse in the brain that resulted in the formation of GS, followed by a relapse in the bone marrow. The remaining patient developed an optic nerve GS after suffering a bone marrow relapse. All three patients received irradiation for the GS and systemic chemotherapy before the allo-BMT. TBI was used for conditioning, and GVHD prophylaxis was with cyclosporine (CsA) and short-term MTX in all three cases. These patients are currently 9 to 37 months post-BMT without relapse. Thus, our experience suggests that allo-BMT is an effective treatment for AML patients with existing or pre-existing intracerebral GS.     

Role of factor VIII on activated protein C resistance ratio in inflammatory diseases

Therapeutic options for treatment of recurrence of leukaemia after allogeneic bone marrow transplantation (BMT) are limited. A beneficial effect of donor lymphocyte infusions (DLI) has not previously been described in acute myeloid leukaemia (AML) relapse. We report a case of AML with t(8;21), relapsing 3 months after BMT, who received DLI without adjuvant chemotherapy or growth factors. The patient developed acute GVHD and achieved a rapid complete remission of his AML by both cytologic and molecular criteria of at least 14 months duration, thereby showing that DLI for AML in relapse after BMT is an alternative therapeutic option.     

Secondary acute leukemia following mitoxantrone-based high-dose chemotherapy for primary breast cancer patients

The incidence of secondary myelodysplasia/acute myeloid leukemia (AML) was retrospectively assessed in an international joint study in 305 node-positive breast cancer patients, who received mitoxantrone-based high-dose chemotherapy (HDCT) followed by autologous stem cell support as adjuvant therapy. The median age of the patients was 57 years (range 22-67). In all, 268 patients received peripheral blood stem cells, and 47 patients received autologous bone marrow. After a median follow-up of 57 months (range 10-125), three cases of secondary AML (sAML) were observed, resulting in a cumulative incidence of 0.94%. One case of sAML developed 18 months after HDCT (FAB M3) The karyotype was translocation 15;17 and, after induction therapy, the patient underwent autologous stem cell transplantation, and is in complete remission (CR) of both breast cancer and AML. The second patient developed AML (FAB M4eo with inversion 16) 5 months after HDCT. This patient achieved CR after induction therapy, but died of infectious complication. A third patient developed AML (FAB M4) 6 months after HDCT. She achieved CR after induction therapy, but relapsed and expired 28 months after diagnosis of AML. sAML after mitoxantrone-based HDCT is a possible, but rare complication in breast cancer patients.     

Monoclonal antibody purging and autologous bone marrow transplantation in acute myelogenous leukemia in complete remission

A mouse monoclonal antibody (S4-7) reacting with human myelomonocytic cells has been previously shown to be suitable for bone marrow purging in selected acute myelogenous leukemia (AML) patients with S4-7 positive leukemic clonogenic cells at diagnosis. The results obtained in seven AML patients who underwent such a treatment, followed by autologous bone marrow transplantation (ABMT), are now reported. Six patients underwent ABMT in first complete remission (CR), one in second CR, after BAVC conditioning regimen. One patient died of infection 1 month after ABMT; in the other six a complete recovery of hemopoiesis was observed. In spite of S4-7 reactivity with normal myelomonocytic cells, a prompt recovery of granulopoiesis was however observed both in in vitro liquid culture and in vivo with a median time of 20 days to reach granulocyte values of 500 x 10(6)/l. The patient transplanted in 2nd CR relapsed 3 months after ABMT. Of the five evaluable patients transplanted in 1st CR, two relapsed 8 and 9 months post-ABMT while three remain in continuous CR at 35, 47, 57 months. Leukemic cells of two of the three patients with recurrent disease were studied at relapse and in both could be detected a significant percentage of S4-7 negative cells, detectable neither at diagnosis nor (one patient) at the time of first relapse after standard chemotherapy.     

Acute Myelogenous Leukemia With PIG-A Gene Mutation Evolved from Aplastic Anemia—Paroxysmal Nocturnal Hemoglobinuria Syndrome

We report a patient with aplastic anemia (AA)-paroxysmal nocturnal hemoglobinuria (PNH) syndrome who developed acute myelogenous leukemia (AML). Flow cytometric analysis showed that the leukemic cells in the bone marrow lacked CD59 antigen on their surface and were positive for P-glycoprotein. Heteroduplex and single-strand conformation polymorphism analysis followed by sequencing of the leukemic cells in the bone marrow disclosed 1 frameshift-type mutation in exon 2 of the phosphatidylinositol glycan-class A (PIG-A) gene, which deductively produces truncated PIG-A protein. These findings provide direct evidence that the leukemic cells evolved from the affected PNH clone. Cytogenetic analysis in the bone marrow in each stage of AA-PNH, AML, and at relapse of AML showed normal, -7, and -7 plus -20, respectively, showing evidence of a clonal evolution. Because complete remission of AML was not achieved by intensive chemotherapies, allogeneic peripheral blood stem cell transplantation (PBSCT) from the patient's HLA-matched sister was performed successfully with recovery of CD59 antigen on bone marrow hematopoietic cells; however, leukemia relapsed 4 months after PBSCT. Leukemia derived from PNH may be resistant to intensive chemotherapy, and a highly myeloablative regimen may be required for stem cell transplantation to eradicate the PNH-derived leukemia clone.     

Factors affecting the outcome of allogeneic bone marrow transplantation for adult patients with refractory or relapsed acute leukaemia

We evaluated the outcome of allogeneic bone marrow transplantation (BMT) for advanced acute myeloid leukaemia (AML) and acute lymphoblastic leukaemia (ALL) in 383 adult patients in nine Australian adult BMT centres between 1981 and 1997. The median overall survival for the group was 4.8 months, with an estimated 5-year survival of 18%. 28% of patients died of transplant-related toxicities within the first 100 d. Progressive disease was responsible for 48% of deaths. Multi-factor analysis demonstrated that AML (v ALL), disease status (second complete remission [CR2] v others), age (< 40 years) and duration of prior first complete remission (CR1) (> 6 months) were pre-transplant variables significantly associated with improved survival. Acute graft-versus-host disease (GVHD) of any grade reduced the rate of relapse in both AML and ALL, but only grades I-II were associated with improved survival. Both limited and extensive chronic GVHD were associated with increased survival. Only patients with AML in untreated first relapse or CR2, with a duration of CR1 > 6 months, or patients with T ALL, had a 5-year survival > 20%. Transplants for AML in induction failure or pre-B ALL in untreated first relapse or CR2 had an intermediate outcome, with 5-year survival of 10-20%. A 5-year survival of < 10% was observed for patients transplanted for ALL in induction failure or for pre-B ALL or AML in refractory first relapse or beyond CR2. These results suggest that for most adult patients with advanced acute leukaemia an allograft offers only a small chance of cure.     

Donor lymphocyte infusion induced molecular remission in relapse of acute myeloid leukaemia after allogeneic bone marrow transplantation.

Donor lymphocyte infusion (DLI) has been used successfully to induce remissions in relapse of acute myeloid leukaemia (AML) after bone marrow transplantation (BMT), but molecular eradication of leukaemia has rarely been documented. A patient with AML-M4Eo relapsed after HLA-identical sibling BMT in first complete remission (CR). Cytogenetic and molecular genetic investigations confirmed inv(16) and CBFbeta/MYH11 fusion characteristic of M4Eo. A second remission was obtained with chemotherapy. Full donor chimerism was demonstrated by fluorescence in situ hybridisation. However, molecular evidence of minimal residual disease still persisted, and donor lymphocyte infusion (DLI) was administered. This resulted in molecular eradication, and the patient remained in clinical and molecular remission 16 months from DLI. Our observations showed that, for AML relapse after BMT, molecular leukaemia eradication could be achieved by DLI so that, in cases where genetic markers are available, molecular monitoring should be performed to assess the efficacy of treatment.     

Bone marrow vs extramedullary relapse of acute leukemia after allogeneic hematopoietic cell transplantation: risk factors and clinical course

A total of 118 consecutive adult patients with acute leukemia (78 AML, 36 ALL, and four acute mixed lineage leukemia) underwent allogeneic hematopoietic cell transplantation (HCT) after conditioning with BuCy (n=113) or a nonmyeloablative regimen of busulfan-fludarabine (n=5). After a median follow-up of 35.8 months (range, 6.4-91.0), 34 patients experienced at least one episode of leukemia relapse. Of 34 initial episodes, 14 (41%) occurred in extramedullary sites, with (n=8) or without (n=6) concomitant bone marrow involvement. The median time to relapse in the extramedullary sites was longer than that of relapse in bone marrow only (13.5 vs 6.1 months, P=0.046). Acute leukemia subtype and disease status at HCT showed an independent predictive value for overall relapse, as well as for extramedullary relapse with or without bone marrow involvement (Philadelphia chromosome positive acute leukemia vs low-risk AML, relative risk 22.68 (95% CI, 2.18-235.64); other than first CR vs first CR, relative risk 5.61 (95% CI, 1.80-17.51)), but not for bone marrow relapse. Our study suggests that there may be different pathogenetic mechanisms for bone marrow vs extramedullary relapse of acute leukemia after allogeneic HCT. The mode of relapse needs to be investigated in future reports of acute leukemia treated with allogeneic HCT.     

Influence of karyotype on outcome of allogeneic bone marrow transplantation for adults with precursor B-lineage acute lymphoblastic leukaemia in first or second remission

The prognostic relevance of karyotype has been established in adult acute lymphoblastic leukaemia (ALL) patients treated with chemotherapy but not definitively evaluated in an allogeneic bone marrow transplantation (BMT) setting. To determine the factors affecting the outcome of allogeneic BMT for adults with precursor B-lineage ALL in first or second complete remission (CR), a total of 41 consecutive patients with a successful karyotype were enrolled in this study. There were 21 men and 20 women with a median age of 27 (15-43) years. The distribution of French-American-British (FAB) subtypes was as follows: L1 (n = 26), L2 (n = 15). Unfavourable karyotypes (n = 12) were defined as Ph+ or t(4;11). Disease status at the time of transplant was first CR (n = 35) or second CR (n = 6). With a median follow-up of 36 months, the 3-year probabilities of relapse and disease-free survival (DFS) were 36.3 +/- 8.4% and 57.3 +/- 8.4% respectively. Potential variables predicting worse relapse and DFS were FAB subtype (L2), extramedullary involvement, pre-BMT status (second CR), unfavourable karyotype and type of graft-versus-host disease (GVHD). Further multivariate analysis showed that karyotype and pre-BMT status were independently associated with relapse and DFS. In addition, chronic GVHD was found to be significantly associated with a lower relapse rate.     

Myelodysplastic relapse of de novo acute myeloid leukaemia with trilineage myelodysplasia: a previously unrecognized correlation

We describe the occurrence of an unusual mode of relapse in six of 24 patients who presented with de novo acute myeloid leukaemia (AML) associated with trilineage myelodysplasia (TMDS). After the induction of complete remission (CR) by intensive chemotherapy in five patients and following bone marrow transplantation (BMT) in one, the myelodysplastic state, but not overt AML, recurred. Relapse of myelodysplasia occurred at a median of 147 weeks (50-520) from presentation and in two instances was followed a year later by AML. In five cases, myelodysplastic relapse was treated with low-dose cytosine arabinoside given alone or with other chemotherapeutic agents. Three patients remain in CR after 1, 2 and 5 years. The reappearance of myelodysplastic features in these six patients was strongly correlated with the presence of TMDS at presentation of the AML. It was not observed once in the 136 AML patients, treated similarly, who did not have associated TMDS at presentation (P less than 0.001). Thus, relapse with myelodysplasia is not an effect of chemotherapy as has been previously postulated.     

Second allogeneic transplantation using umbilical cord blood for a patient with relapsed ALK+ anaplastic large cell lymphoma after allogeneic bone marrow transplantation in the era of ALK inhibitors: A case report

Rationale:Anaplastic lymphoma kinase (ALK) + anaplastic large cell lymphoma (ALCL) is considered as a good prognosis lymphoma. However, in an extremely rare subset of patients, ALK+ ALCL with leukemic presentations is known to be chemotherapy-resistant. Although several novel therapies have been tested, the standard therapy for relapsed/refractory ALK+ ALCL has not been established yet.Patient concerns:An 18-year-old female patient who had conventional chemotherapy- and Brentuximab Vedotin (BV)-resistant ALK+ ALCL with leukemic presentation. She was successfully treated with an ALK inhibitor, crizotinib. Crizotinib induced complete remission (CR) and bridged to allogeneic bone marrow transplantation (BMT).Diagnosis:However, her ALCL relapsed on day 60 after BMT and she developed high grade fever and lymphadenopathy.Intervention:Although crizotinib was given to the patient immediately after relapse, she developed grade 3 nausea and could not continue to take it. Then, we gave alectinib to the patient, which promptly induced sustained CR without any further chemotherapy. The patient received second stem cell transplantation using umbilical cord blood with myeloablative regimen in 2^nd CR.Outcomes:The patient has been in CR under maintenance therapy of alectinib for more than 16 months.Lessons:Both ALK inhibitors demonstrated drastic efficacy for our patient who had chemotherapy- and BV-resistant ALK+ ALCL with leukemic presentation. Alectinib showed less gastro-intestinal toxicity than crizotinib and the patient was able to take it even at the relatively early phase of stem cell transplantation.     

Granulocytic sarcoma of the prostate as the first manifestation of a late relapse of acute myelogenous leukemia

Summary We describe a 68-year-old patient who developed granulocytic sarcoma of the prostate 9 years after complete remission following successful treatment of acute myelogenous leukemia (FAB, M2). PCR analysis of bone marrow samples in first remission and at the time of relapse detected an AML1/ETO rearrangement typical for AMLs with t (8; 21). The CD 56 antigen was not expressed on the leukemic cells. Systemic chemotherapy led to a short-lasting regression of the tumor, but the patient subsequently developed overt bone marrow relapse and died during chemotherapy. While granulocytic sarcoma as a primary manifestation of AML is well known, as the first manifestation of relapse it appears to be very uncommon.     

CD 56-positive acute myeloid leukemia (AML-M 1) with t(16;21) (p11;q22) presenting an extramedullary tumor in the right breast at relapse

A 46-year-old woman was diagnosed as having acute myeloid leukemia (M 1) with translocation t(16;21) (p11;q22). The leukemic cells were positive for CD 13, CD 33, CD 34, CD 41, CD 56 and HLA-DR. After induction chemotherapy, the patient achieved complete remission (CR). However, 8 months later she relapsed with various additional chromosomal abnormalities. Although the patient achieved a 2nd CR after re-induction chemotherapy, the patient had extramedullary tumors in the right breast twice and relapse occurred frequently. The tumor cells were characterized by the same immunophenotypes and t(16;21) with additional 1 q trisomy. Although there was no evidence of hematological relapse, another type of 1 q trisomy was observed. Furthermore, an increase of abnormalities with 1 q trisomy was noted concomitant with re-increase in the number of blasts. The patient underwent allogeneic bone marrow transplantation (BMT), but she died from BMT complications. The case could have been a karyotype of t(16;21) with additional chromosomal abnormalities through consecutive approaches. Because of the high occurrence rate of relapse, we consider various additional chromosomal abnormalities and the expression of CD 56 as prognostic factors of this condition.     

Long-term remission of APL with a second allogeneic BMT after CNS relapse following HLA-identical allogeneic BMT

Second allogeneic bone marrow transplantation (BMT) for AML relapsing after an initial BMT has a poor prognosis, with a probability of a 2-y disease-free survival below 30 per cent, caused both by treatment-related mortality (TRM) and high relapse rate. While TRM is most likely due to heavy pretreatment, AML relapse after BMT may be due to resistant disease or to a poor graft-versus-leukaemia (GvL) effect of the transplant. The degree of GvL may depend on individual donor/recipient immunoreactivity. In most published cases of second allogeneic BMT, both transplants were performed from the same donor. Here, we describe a patient who was first transplanted for acute promyelocytic leukaemia (APL) (AML FAB M3v) from his HLA-identical brother and received intensive immunotherapy including donor lymphocytes and IL2. He remained free from GvHD >I degrees, but developed CNS relapse. After a second BMT from another HLA-identical brother, he spontaneously developed GvHD III degrees, and has now been disease free for nearly 3 years. In this patient, long-term remission of AML relapsing after BMT was achieved by combining remission induction using an individual chemotherapy protocol with a second BMT from an alternative matched related donor and transient GvHD III degrees, which probably conferred a GVL effect.     

Origin of leukemic relapse after bone marrow transplantation: comparison of cytogenetic and molecular analyses

Leukemic relapse following bone marrow transplant (BMT) is generally due to the recurrence in recipient cells, but may rarely occur as a result of donor cell transformation. Donor cell relapse is generally identified using cytogenetic markers such as the sex chromosomes. Recently, molecular techniques have been used to identify the origin of bone marrow cells by their DNA restriction fragment length polymorphisms. We describe the case of a male pediatric patient who had a leukemic relapse 30 months following BMT from his sister. Both cytogenetic and molecular techniques were used to identify the origin of the leukemic relapse. Cytogenetic analyses indicated the absence of the Y chromosome and the presence of a donor cell type 9qh polymorphism, suggesting a donor cell relapse. Molecular analyses also indicated the absence of the Y chromosome but demonstrated the recurrence of recipient DNA markers from three other chromosomes, suggesting a recipient cell relapse. While the leukemic cell lineage cannot be definitively assigned in this case, our results suggest that caution must be exercised when assigning leukemic cell lineage following post-BMT relapse.     

Bone marrow transplantation for patients with Philadelphia chromosome-positive acute lymphoblastic leukemia

We reported the results of 6 allogenic bone marrow transplantation (BMT) and 3 autologous BMT for patients with Philadelphia chromosome (Ph1)-positive acute lymphoblastic leukemia (ALL) by Nagoya BMT group. Two of six patients who received allogenic BMT have continued complete remission (CR) on +639 days and +1,597 days. Four of six patients relapsed on +134, +203, +216, and +267 days. Two patients with a disease-free survival for a long time had both acute and chronic GVHD. It is suggested that graft-versus-leukemia (GVL) effect might prevent the relapse. On the contrary, one patient who received with monoclonal antibodies plus complement-treated autologous bone marrow is free of leukemia on +439 days. Our results suggest the follows. 1) We do chromosomal analysis at initial diagnosis in all cases to do BMT in first CR. 2) We intensify the conditioning regimen for BMT. 3) We study on application of GVL effect to prevent the relapse. 4) We establish the best purging method to eradicate residual leukemic cells for autologous BMT. 5) We do allogenic BMT using HLA-matched unrelated donor for patients without related donor.     

Reciprocal bone marrow transplantation between brother and sister

A child with AML underwent allogeneic BMT from an HLA-identical sister donor. Prompt and stable triline-age engraftment occurred and after few months he returned to a normal life. Eight years later a primary NHL of bone developed in his sister. A partial remission was obtained by means of standard NHL treatment, but 3 months later rapid disease progression occurred with complete bone marrow invasion (ALL-L3). She was treated with a leukemia relapse protocol, obtaining a second partial remission. Unpurged bone marrow harvested from the brother, transplanted for AML 8 years earlier, was infused after conditioning with TBI and thiothepa. No GVHD prophylaxis was given. Neutrophil engraftment occurred by 14 days and platelet engraftment by 20 days after BMT. No acute GVHD was observed, but unexpectedly she developed skin and liver GVHD-like symptoms 80 days after BMT. Since the liver biopsy was suggestive of liver GVHD and in the absence of any other evidence as a possible cause of the hepatic damage, the patient started mycophenolate. Two months later serum hepatitis B markers were detectable.