Results of allogeneic bone marrow transplants for leukemia using donors other than HLA-identical siblings

PURPOSE: To compare outcomes of bone marrow transplants for leukemia from HLA-identical siblings, haploidentical HLA-mismatched relatives, and HLA-matched and mismatched unrelated donors. PATIENTS: A total of 2,055 recipients of allogeneic bone marrow transplants for chronic myelogenous leukemia (CML), acute myelogenous leukemia (AML), and acute lymphoblastic leukemia (ALL) were entered onto the study. Transplants were performed between 1985 and 1991 and reported to the International Bone Marrow Transplant Registry (IBMTR). Donors were HLA-identical siblings (n = 1,224); haploidentical relatives mismatched for one (n = 238) or two (n = 102) HLA-A, -B, or -DR antigens; or unrelated persons who were HLA-matched (n = 383) or mismatched for one HLA-A, -B, or -DR antigen (n = 108). HLA typing was performed using serologic techniques. RESULTS: Transplant-related mortality was significantly higher after alternative donor transplants than after HLA-identical sibling transplants. Among patients with early leukemia (CML in chronic phase or acute leukemia in first remission), 3-year transplant-related mortality (+/-SE) was 21% +/- 2% after HLA-identical sibling transplants and greater than 50% after all types of alternative donor transplants studied. Among patients with early leukemia, relative risks of treatment failure (inverse of leukemia-free survival), using HLA-identical sibling transplants as the reference group, were 2.43 (P < .0001) with 1-HLA-antigen-mismatched related donors, 3.79 (P < .0001) with 2-HLA-antigen-mismatched related donors, 2.11 (P < .0001) with HLA-matched unrelated donors, and 3.33 (P < .0001) with 1-HLA-antigen-mismatched unrelated donors. For patients with more advanced leukemia, differences in treatment failure were less striking: 1-HLA-antigen-mismatched relatives, 1.22 (P = not significant [NS]); 2-HLA-antigen-mismatched relatives, 1.81 (P < .0001); HLA-matched unrelated donors, 1.39 (P = .002); and 1-HLA-antigen-mismatched unrelated donors, 1.63 (P = .002). CONCLUSION: Although transplants from alternative donors are effective in some patients with leukemia, treatment failure is higher than after HLA-identical sibling transplants. Outcome depends on leukemia state, donor-recipient relationship, and degree of HLA matching. In early leukemia, alternative donor transplants have a more than twofold increased risk of treatment failure compared with HLA-identical sibling transplants. This difference is less in advanced leukemia.     

Lymphoblastoid human interferon and low dose IL-2 combined with donor lymphocyte infusion as therapy of a third relapse of CML--a case report

A patient, who was treated twice with donor lymphocyte infusions for relapse of CML after an allogeneic BMT was given lymphoblastoid human alpha-IFN after a third relapse. Further donor lymphocyte infusions were followed by repeated courses of 30 days treatment with a low dosage of IL-2 subcutaneously, alternately with alpha-IFN. This treatment resulted in a hematologic and cytogenetic remission. He also developed a limited degree of chronic GVHD. At the latest follow-up at 20 months after the third course of lymphocyte infusions he is in continuous hematologic and cytogenetic remission. Furthermore, a qualitative PCR analysis for the bcr/abl translocation is negative.     

Prevalence of antibodies to Rickettsia conorii Ricketsia africae, Rickettsia typhi and Coxiella burnetii in Mauritania

A 24-year-old male developed cytogenetic relapse of chronic myeloid leukemia (CML) four years after allogeneic BMT. After a year of treatment with IFN-alpha, he achieved a partial cytogenetic response. Treatment with donor leukocyte infusions (DLI) was given (total dose 1 x 10(8) T lymphocytes/kg). Two months later, he developed acute GVHD (skin and liver), that improved with CsA and methylprednisolone and resulted in cytogenetic remission with complete donor chimerism. One month later he developed rhinocerebral mucormycosis and was successfully treated with surgical debridement and liposomal amphotericin B (total dose 12 g). This is the first case of mucormycosis described after DLI.     

Tactical vs. other simulated aerial combat maneuvers

We report here that a patient with relapsed AML after allogeneic bone marrow transplantation achieved and maintained complete remission (CR) after effective donor leukocyte transfusion (DLT), without the occurrence of GVHD and marrow aplasia, for more than 21 months. This continuous CR maintenance is mainly due to the application of DLT at molecular relapse that was diagnosed by monitoring minimal residual disease (MRD) by the quantitation of WT1 (Wilms tumor gene) expression levels (WT1 assay). The present case demonstrates that early application of DLT at molecular relapse is essential for the improvement of the efficacy of DLT for relapsed AML after BMT.     

Indications, technique and risks in bone marrow transplantation in adulthood

The option of bone marrow transplantation (BMT) significantly improved prognosis of adult patients with hematologic malignancies aged less than 50 years. Allogeneic BMT using the marrow of an HLA-identical family member still provides the most effective method of BMT. Conventional indications for this form of BMT are chronic myeloid leukemia (CML), acute leukemias presenting with adverse risk factors, myelodysplastic syndromes and severe aplastic anemia. If performed early in the disease course (e.g. during the chronic phase of CML or first remission of acute leukemia and MDS) allogeneic BMT cures 50 to 60% of patients. About 20% die of therapy related complications, e.g. graft versus host disease (GvHD), fatal infections or venoocclusive disease of the liver (VOD) and about 20% of patients succumb to relapse of their hematologic disorder. 80% presenting with severe aplastic anemia can be cured, if allogeneic BMT is performed soon after diagnosis without previous immunosuppressive therapy and blood transfusions. BMT with the marrow of a matched unrelated donor or autologous BMT are increasingly used as alternative procedures. A rate of lethal complications as high as 50% hinders rapid extension of BMT with unrelated donors. Therefore, this form of BMT should be restricted to young patients with leukemias, who cannot achieve long-term remission with conventional chemotherapy (in case of acute leukemias) or alpha-interferon (in case of CML). Reconstitution of hematopoiesis is more rapid after peripheral blood stem cell transplantation (PBSCT) compared with autologous BMT. Therefore, PBSCT will replace autologous BMT in most cases. Most favourable results of PBSCT have been reported in patients with malignant lymphomas after relapse or inferior response to primary induction therapy. Due to the higher relapse rate autologous BMT is inferior to allogeneic BMT in leukemia patients. Trials are required to clarify the potential role of myeloablative therapy with stem cell support in the treatment of patients with solid tumors. Many of the preliminary results already published are unsatisfactory and data of larger trials are still lacking. Therefore, BMT or PBSCT cannot be recommended generally for the therapy of patients with solid tumors.     

Long-term results after allogeneic bone marrow transplantation for chronic myelogenous leukemia in chronic phase: a report from the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation

The purpose of this study was to determine the long-term results of allogeneic bone marrow transplantation for chronic myeloid leukemia. A retrospective analysis was carried out of the outcome of 373 consecutive transplants performed at 38 European institutions between 1980 and 1988 and reported to the registry of the European Group for Blood and Marrow Transplantation. All transplants were carried out for first chronic phase of chronic myelogenous leukemia using unmanipulated marow cells from HLA-identical sibling donors. The probability of survival and leukemia-free survival at 8 years were 54% (95% CI: 49-59) and 47% (95% CI: 41-52) respectively. The probabilities of developing acute GVHD (II-IV) at 100 days and chronic GVHD at 4 years after transplant were 47% (95% CI: 41-53) and 52% (95% CI: 46-58) respectively. The probabilities of transplant-related mortality and leukemic relapse 8 years after BMT were 41% (95% CI: 36-48) and 19% (95% CI: 14-25), respectively. Transplant within 12 months of diagnosis was associated with reduced transplant-related mortality (34 vs 45%, P = 0.013) and resulted in improved leukemia-free survival (52 vs 44%, P = 0.03). The probability of relapse was significantly reduced in patients who developed chronic GVHD (RR = 0.33, P = 0.004). The probability of relapse occurring more than 2 years after transplant was increased more than five-fold in patients transplanted from a male donor (RR = 5.5, P = 0.006). Sixty-seven patients in hematologic remission were studied for residual disease by two-step RT/PCR for BCR-ABL mRNA and 61 (91%) tested negative. We conclude that bone marrow transplantation can induce long-term survival in approximately one-half of CML patients; the majority of survivors have no evidence of residual leukemia cells when studied by molecular techniques. The probability of late relapse is increased with use of a male donor.     

Allogeneic peripheral blood progenitor cells for treatment of relapse after bone marrow transplantation

Donor leukocyte infusions (DLI) are an effective therapy for patients who relapse with leukemia after bone marrow transplantation (BMT). Severe graft-versus-host disease and prolonged periods of pancytopenia compromise the success of this treatment in a substantial number of patients. We used filgrastim-mobilized peripheral blood progenitor cells (PBPCs), in some cases preceded by cytoreductive therapy, to circumvent some of the problems associated with DLI. Eleven patients (median age 41 years) received a total of 20 donor cell infusions. Their diagnosis was CML in hematological (two patients) or cytogenetic relapse (two patients), six patients suffered from acute myeloid leukemia (AM; n = 5) or Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL Ph+). One patient had multiple myeloma (MM). All six patients with acute leukemias received cytoreductive therapy prior to PBPC infusions; three patients with CML were pretreated with IFN alpha. Four of four patients with CML responded to PBPC infusions and currently are in complete clinical and molecular remission for time periods between 1 and 12 months. Six of six patients with acute leukemias achieved a complete remission. All of them relapsed after a median remission duration of 24 weeks (range 11-49 weeks). Three patients relapsed at extramedullary sites (CNS, testes, skin). Four of six acute leukemia patients received further cytoreductive therapy. All patients responded again and are in complete remission for time periods between 14 and 615 days. Two patients with acute leukemias have died due to dissemination of the disease. The patient with MM did not respond and is alive with disease. Severe (grade III) acute GVHD developed in two of 11 patients, three patients developed grade II disease, six patients did not show any signs of GVHD. Extensive chronic GVHD has developed in two cases to date. Patients with chemotherapy prior to PBPC infusion developed neutropenia and thrombocytopenia with a maximum duration of 20 and 14 days, respectively; prolonged periods of neutropenia did not occur. Two patients developed long-lasting thrombocytopenia in spite of PBPC infusion, in one case followed by leukemic relapse. Repeated courses of chemotherapy and PBPC infusion were generally tolerated well; no early deaths due to treatment-related toxicity or GVHD were observed. We conclude that the use of allogeneic PBPC instead of DLI in patients with relapse after BMT is technically feasible and safe. The efficacy of PBPC infusions seems comparable to DLI in patients with CML. Patients with acute leukemias also achieved complete albeit transient remissions. Aggressive chemotherapy followed by PBPC infusions resulted in only limited duration of cytopenia. The usage of PBPC infusion instead of non G-CSF-mobilized donor cells for treatment of relapse after BMT may reduce pancytopenia-related complications and merits further investigation.     

Treatment of relapse after allogeneic BMT with donor leukocyte infusions in 16 patients

Sixteen patients with relapse after allogeneic BMT were treated with donor leukocyte infusions (DLI) from the original donor. The diagnoses at relapse were: CML in chronic phase (CP) (two patients), CML in accelerated phase (AP) (four patients), AML (four patients), MDS (one patient), ALL (four patients) and relapse of Hodgkin's disease (one patient). The patients received a mean of 5.2 x 10(8) leukocytes/kg with a range of 1.4-12.3 x 10(8) leukocytes/kg. Six patients obtained complete remission (CR), one with CML in CP, three with CML in AP, one MDS and one ALL. Partial remission (PR) was seen in three patients, one patient with CML in AP, one with AML and one with Hodgkin's disease. Seven patients had no response (NR) to the infusions, including one patient with CML in CP transplanted with a syngeneic donor. Four patients developed marrow hypoplasia after DLI (three CR and one PR) and two patients (ALL with CR and MDS with CR) were hypoplastic at relapse and marrow hypoplasia continued after DLI. GVHD occurred without GVL, but GVL only occurred in one patient with absence of GVHD. Eleven patients died of leukemia, six patients are alive. Three patients with CML are in CR 12, 12 and 32 months after DLI and one patient with ALL is in CR 15 months after DLI.     

Successful donor leukocyte infusion for chronic myeloid leukemia relapsing in accelerated phase after T cell-replete unrelated marrow transplantation

A 47-year-old man relapsed with accelerated phase CML 19 months after a T cell-replete unrelated BMT. Three donor leukocyte infusions (DLI) from the original donor resulted in durable complete hematological and cytogenetic remission. Moderate GVHD developed but was steroid responsive. This report suggests that DLI can be administered safely to patients relapsing after unmodified unrelated allografts. In the patient described, DLI exerted an antileukemic effect sufficiently potent to reverse accelerated phase disease.     

Bone marrow transplants from unrelated donors for patients with chronic myeloid leukemia

BACKGROUND: Chronic myeloid leukemia can be cured by marrow transplantation from an HLA-identical sibling donor. The use of transplants from unrelated donors is an option for the 70 percent of patients without an HLA-identical sibling, but the morbidity and mortality associated with such transplants have been cause for concern. We analyzed the safety and efficacy of transplants from unrelated donors for the treatment of chronic myeloid leukemia and identified variables that predict a favorable outcome. METHODS: Between May 1985 and December 1994, 196 patients with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase received marrow transplants from unrelated donors. RESULTS: The median follow-up was 5 years (range, 1.2 to 10.1). Graft failure occurred in 5 percent of patients who could be evaluated. Acute graft-versus-host disease of grade III or IV severity was observed in 35 percent of patients who received HLA-matched transplants, and the estimated cumulative incidence of relapse at five years was 10 percent. The Kaplan-Meier estimate of survival at five years was 57 percent. Survival was adversely affected by an interval from diagnosis to transplantation of one year or more, an HLA-DRB1 mismatch, a high body-weight index, and an age of more than 50 years. Survival was improved by the prophylactic use of fluconazole and ganciclovir. The Kaplan-Meier estimate of survival at five years was 74 percent (95 percent confidence interval, 62 to 86 percent) for patients who were 50 years of age or younger who received a transplant from an HLA-matched donor within one year after diagnosis. CONCLUSIONS: Transplantation of marrow from an HLA-matched, unrelated donor is safe and effective therapy for selected patients with chronic myeloid leukemia.     

A study of the changes during heating of paracetamol

Fanconi anaemia (FA) is an accepted indication for treatment with allogeneic HLA-identical BMT. Most patients, however, lack a suitable HLA-identical donor. In our centre, six FA patients were transplanted with a matched unrelated donor. Due to hypersensitivity to DNA cross-linking agents, a low-dose cyclophosphamide (CY) and thoraco-abdominal irradiation (TAI) regimen is recommended for conditioning in FA. We added Ara-C upfront and anti-T cell antibodies to enhance engraftment and to prevent GVHD, in combination with T cell depletion in four out of six of the first transplants. One patient did not engraft. In three patients rejection was observed. In three of these four patients a second BMT, using full bone marrow grafts, resulted in successful engraftment. The other patient died before a second BMT could be performed. The incidence and severity of acute GVHD was low: only one patient with grade III acute GVHD was seen. Two out of four surviving patients suffered from chronic GVHD. Four patients survived (median survival time 43 months after BMT), three with good and one with acceptable quality of life. Two patients died, one patient due to adenoviral reactivation with multi-organ failure, and one due to sepsis complicated by ARDS. In conclusion, MUD BMT is feasible in FA patients with bone marrow failure in whom no HLA-identical sibling donor is available. In our study group, the major problem was graft rejection, despite the administration of a combination of graft enhancing anti-T cell antibodies. Multicentre studies are needed to determine a more intensive, but still tolerable, conditioning regimen.     

Screening for CMV-specific T cell proliferation to identify patients at risk of developing late onset CMV disease

Thirty patients undergoing allogeneic BMT were screened post-transplant together with their marrow donors for CMV-specific T cell proliferation and the occurrence of CMV disease. Twenty-one of these patients received a marrow transplant from an HLA-matched sibling donor, and nine from an HLA-matched unrelated donor. All these patients were either CMV seropositive and/or had received a transplant from a CMV-seropositive donor. Patients were monitored for CMV-viraemia until day +100 post-BMT by PCR and virus culture, and thereafter by virus culture only when clinically indicated. The proliferative T cell response was investigated at regular monthly intervals beginning on day +30. A proliferative response to HCMV (median, day +123) was documented in these patients between day +37 and +730 post-BMT. None of the patients with a documented CMV-specific T cell proliferation on day 120 (n = 17) developed CMV disease in the later post-transplant period, but of the patients lacking CMV-specific proliferation (n = 13), 30.8% developed CMV disease after day 120. Thus, patients lacking a CMV-specific T-helper cell response might benefit from sensitive screening for CMV infection and pre-emptive therapy after day +100.     

Adoptive immunotherapy with donor mononuclear cell infusions to treat relapse of acute leukemia or myelodysplasia after allogeneic bone marrow transplantation

Relapse remains a significant problem after allogeneic bone marrow transplantation (BMT). For patients with relapsed chronic myelogenous leukemia (CML), infusions of donor mononuclear cells (MNC) provide a potent graft-versus-leukemia (GVL) reaction inducing complete remissions in the majority of patients. Little is known about the efficacy of donor MNC infusions for patients who relapse with other diseases. We have studied the GVL effects of donor MNC in eight patients with relapsed acute leukemia or myelodysplasia (MDS). One patient with relapsed MDS achieved complete remission and another patient had a transient response. Five of six non-responders died of progressive leukemia and one non-responder died of complications during second BMT. Three patients developed grade I-II acute GVHD responsive to immunosuppression. These data, and review of the literature, suggest that GVL induction with donor MNC infusions is less effective for patients with relapsed acute leukemia than for patients with relapsed CML; too few patients with relapsed MDS have been treated to draw definite conclusions. However, some patients respond, and given the high mortality associated with alternative procedures such as second BMT, donor MNC infusions are a reasonable approach for relapsed acute leukemia and MDS after allogeneic BMT.     

4-Hydroxynonenal and cell signalling

Donor leukocyte transfusions (DLT) have an anti-leukemic effect in most patients with a relapse of chronic myeloid leukemia (CML) after allogeneic stem cell transplantation. However, DLT are often complicated by graft-versus-host disease. Selection of donor lymphocytes with a relative specificity for leukemic cells is desirable. The generation of leukemia-reactive cytotoxic T lymphocyte (CTL) responses between HLA-identical donors and patients in bulk cultures showed major variations, and false negative results were observed. In a modification of a limiting dilution analysis (LDA) two-fold serial dilutions of HLA-identical donor mononuclear cells (MNC) were cultured in the presence of CML cells. The anti-leukemic CTL precursor frequencies in these donors varied between <1 and 9 per 106 MNC. HLA-restricted CD4+ or CD8+ lymphocytes as well as MHC non-restricted gammadelta T cells were responsible for the anti-leukemic responses. A positive correlation between cytotoxicity in the various wells after 3, 4 and 5 weeks of culture could be found. The LDA may be superior to bulk cultures in selecting stable immune responses and in separating multiple different anti-leukemic T cell responses in each donor-patient combination.     

Fulminant, CMV-associated, haemophagocytic syndrome following unrelated bone marrow transplantation

We report a case of haemophagocytic syndrome (HPS) occurring after allogeneic bone marrow transplantation (BMT) for acute promyelocytic leukaemia (APL) in a patient in fourth complete remission (CR). Anti-cytomegalovirus (CMV) antibody (Ab) was negative in this patient before BMT. BMT was performed from an HLA-identical unrelated donor who was positive for CMV Ab. After bone marrow engraftment and haematological recovery, severe acute graft-versus-host disease (GVHD) developed. This patient was treated with methylprednisolone in addition to cyclosporin A (CsA). Acute GVHD showed partial improvement, but CMV antigenaemia was observed. Despite administration of gancyclovir and immunoglobulin, CMV antigenaemia showed no improvement and HPS developed. As no other infections or malignancies were observed, we suspect that CMV infection was the trigger for development of HPS.     

Allogeneic transplantation combining mobilized blood and bone marrow in patients with refractory hematologic malignancies

BACKGROUND: Mobilized blood stem cells have been used successfully in autologous transplant recipients to reduce the complications of pancytopenia due to dose-intensive chemotherapy. Reports of cytokine-mobilized blood progenitor cells in allogeneic transplant recipients are rare. STUDY DESIGN AND METHODS: This is a pilot trial of six patients. Patients with advanced hematologic malignancy received bone marrow (median total 2.6 x 10(8) mononuclear cells/kg) followed by four daily transfusions of blood (median total 9.5 x 10(8) mononuclear cells/kg) from HLA-matched sibling donors who were mobilized with recombinant human granulocyte-colony-stimulating factor (5 micrograms/kg/day subcutaneously for 5 days). All patients received cyclosporine and prednisone for graft-versus-host disease (GVHD) prophylaxis. RESULTS: An absolute neutrophil count greater than 500 per mm3 was achieved on Day 12, and platelet transfusion independence was achieved on Day 16. The median day of hospital discharge was Day 23 after transplant. All patients achieved 100-percent donor cell engraftment. Acute > or = Grade III GVHD did not develop in any patients, but all patients developed Grade I (n = 4) or Grade II (n = 2) acute GVHD. Chronic extensive GVHD developed in four of six patients. One patient died of pneumonia 263 days after transplant while undergoing immune-suppressive therapy for chronic GVHD. CONCLUSION: The transfusion of blood stem cells in patients undergoing allogeneic bone marrow transplant is well tolerated soon after transplant, but the development of chronic GVHD may limit the general usage of unmanipulated blood stem cells.     

Dominant selection system for use in Cryptococcus neoformans

BACKGROUND: Approximately one-fourth of patients who could benefit from bone marrow transplantation (BMT) are served by a genotypically identical sibling donor. When patients do not have an HLA-matched donor, alternative marrow sources should be explored. The way to allow survival in some patients is to perform two- or three loci HLA mismatched BMT. Preliminary results with BMT in partially-matched, related donors performed at Veterans General Hospital-Taipei are reported. METHODS: Between 1985 and 1994, a total of 121 patients were enrolled in this study. Ten patients received BMT with HLA partially-matched, related donor, including 2 acute nonlymphocytic leukemia (ANLL), 5 chronic myelocytic leukemia (CML) and 3 severe aplastic anemia (SAA). Three and four hematologically malignant patients received cyclophosphamide (Cy) + radiotherapy (RT) and Cy + Busulfan(Bu) preconditioning regimens, respectively; three SAA patients received standard Cy + RT regimen. Additional prophylaxis against graft-versus-host disease (GVHD) consisted of methotrexate (MTX) and cyclosporin-A (CSA). The median follow up was 36 months. Seven were 2-loci disparate and 3 were 3-loci. RESULTS: Engraftment developed with a mean of 20.9 days after transplant. Nonengraftment rate was 1/10 (10%), delayed graft failure 2/10(20%) and venoocculsive disease (VOD) 1/10(10%). The percentage of patients who developed grade II to IV acute GVHD was low (13.6% of those mismatched at 0 locus, 31.6% mismatched at 1 loci and 14.3% at > or = 2 loci. p = 0.181). Extensive chronic GVHD occurred in 16.7% (34.1% of those mismatched at 0 locus, 41.2% mismatched at 1 loci and 16.7% at 2 loci. p = 0.492). There were five deaths. The other 5 still survived at 36 months of follow-up. Log-rank analysis revealed no statistical significance between those mismatched at > or = 2 vs at 1 (p = 0.146) but the difference between those mismatched at > or = 2 and at 0 (p = 0.0359) was statistically significant. CONCLUSIONS: When patients requiring BMT without an HLA identical sibling donor, an alternative transplant from haploidentical family members remains a viable option, especially when a patient has CML, SAA or other refractory hematologic malignancies.     

A novel antithrombin gene mutation: slippage and mispairing as a mechanism of genetic disease

Treatment options for acute leukemia relapsing after allogeneic BMT include conventional chemotherapy or a second transplant; however, results are rather discouraging, the first option being associated with poor survival and the second with a high mortality rate. More recently, donor leukocyte infusion (DLI) from the original donor has been used for relapsed patients in an attempt to induce a graft-versus-leukemia (GVL) effect. This procedure is partially devoid of the toxicity inherent to a second BMT. At our Institution, a 36-year-old patient with biphenotypic AML in second complete remission after relapse following allogeneic BMT was treated with peripheral blood stem cell (PBSC)-enriched donor leukocytes, obtained after in vivo priming with rhG-CSF. The patient experienced extensive cGVHD but developed a testicular relapse while in full hematologic remission. After irradiation of the sanctuary site he remains free of disease, still with chronic GVHD, 21 months after bone marrow relapse. This case suggests that immunologically privileged sites are inaccessible to GVHD/GVL effect. This should be considered when planning salvage transplants procedures in patients at risk for extramedullary involvement.