Mobilization of healthy donors with plerixafor affects the cellular composition of T-cell receptor (TCR)-αβ/CD19-depleted haploidentical stem cell grafts

Background: HLA-haploidentical hematopoietic stem cell transplantation (HSCT) is suitable for patients lacking related or unrelated HLA-matched donors. Herein, we investigated whether plerixafor (MZ), as an adjunct to G-CSF, facilitated the collection of mega-doses of hematopoietic stem cells (HSC) for TCR-αβ/CD19-depleted haploidentical HSCT, and how this agent affects the cellular graft composition. Methods: Ninety healthy donors were evaluated. Single-dose MZ was given to 30 ‘poor mobilizers’ (PM) failing to attain ≥40 CD34+ HSCs/μL after 4 daily G-CSF doses and/or with predicted apheresis yields ≤12.0x106 CD34+ cells/kg recipient’s body weight. Results: MZ significantly increased CD34+ counts in PM. Naïve/memory T and B cells, as well as natural killer (NK) cells, myeloid/plasmacytoid dendritic cells (DCs), were unchanged compared with baseline. MZ did not further promote the G-CSF-induced mobilization of CD16+ monocytes and the down-regulation of IFN-γ production by T cells. HSC grafts harvested after G-CSF + MZ were enriched in myeloid and plasmacytoid DCs, but contained low numbers of pro-inflammatory 6-sulfo-LacNAc+ (Slan)-DCs. Finally, children transplanted with G-CSF + MZ-mobilized grafts received greater numbers of monocytes, myeloid and plasmacytoid DCs, but lower numbers of NK cells, NK-like T cells and Slan-DCs. Conclusions: MZ facilitates the collection of mega-doses of CD34+ HSCs for haploidentical HSCT, while affecting graft composition

Clonal karyotypic hematopoietic cell abnormalities occurring after autologous bone marrow transplantation for Hodgkin's disease and non- Hodgkin's lymphoma

Abstract Over a 6-year period, 275 patients were treated with autologous bone marrow transplantation (auto-BMT) for advanced-stage malignant lymphoma. After BMT, clonal chromosomal abnormalities were detected in hematopoietic cells from 10 patients. All 10 had morphologically and cytogenetically normal BMs at the time of stem cell harvest. The cytogenetic changes were first detected 1.8 to 6.5 years (mean, 3.9) after induction chemotherapy, and 0.5 to 3.1 years (mean, 1.4) after transplantation, and were characteristic of those reported for therapy- related myelodysplastic syndrome (MDS) in 9 of the patients: abnormalities of chromosome 5 or 7 (classical-form) were present in 4, 11q23 or 21q22 abnormalities (topoisomerase II-related form) were detected in 3, and a combination of both forms was seen in 2 patients. Clonal 2p abnormalities were found in the 1 remaining patient. The abnormal karyotypes were associated with morphologically recognizable MDS in 3 patients and with acute myeloid leukemia (AML) arising in MDS in 2. Four of these patients have died: 3 of AML and 1 of infection. One patient is still alive with cytopenia. The clonal cytogenetic abnormalities were not associated with MDS in 5 patients: 1 has died of recurrent lymphoma, 2 have cytopenia, and 2 still have no morphologic or clinical evidence of MDS after short follow-up (4 and 13 months). Compared with a control group matched for disease, length of follow-up, and treatment with auto-BMT, there were no statistically significant associations between the development of clonal chromosomal abnormalities and age, number of chemotherapeutic regimens, prior local radiation, BMT conditioning regimen (with or without total body irradiation), or type of lymphoma. These studies show that the risk of developing clonal cytogenetic changes after auto-BMT for malignant lymphoma is approximately 9% at 3 years, even when pre-BMT karyotypic studies are normal. The exact significance of these cytogenetic abnormalities in the absence of MDS or AML is unclear.</jats:p

Clonal karyotypic hematopoietic cell abnormalities occurring after autologous bone marrow transplantation for Hodgkin's disease and non- Hodgkin's lymphoma

Over a 6-year period, 275 patients were treated with autologous bone marrow transplantation (auto-BMT) for advanced-stage malignant lymphoma. After BMT, clonal chromosomal abnormalities were detected in hematopoietic cells from 10 patients. All 10 had morphologically and cytogenetically normal BMs at the time of stem cell harvest. The cytogenetic changes were first detected 1.8 to 6.5 years (mean, 3.9) after induction chemotherapy, and 0.5 to 3.1 years (mean, 1.4) after transplantation, and were characteristic of those reported for therapy- related myelodysplastic syndrome (MDS) in 9 of the patients: abnormalities of chromosome 5 or 7 (classical-form) were present in 4, 11q23 or 21q22 abnormalities (topoisomerase II-related form) were detected in 3, and a combination of both forms was seen in 2 patients. Clonal 2p abnormalities were found in the 1 remaining patient. The abnormal karyotypes were associated with morphologically recognizable MDS in 3 patients and with acute myeloid leukemia (AML) arising in MDS in 2. Four of these patients have died: 3 of AML and 1 of infection. One patient is still alive with cytopenia. The clonal cytogenetic abnormalities were not associated with MDS in 5 patients: 1 has died of recurrent lymphoma, 2 have cytopenia, and 2 still have no morphologic or clinical evidence of MDS after short follow-up (4 and 13 months). Compared with a control group matched for disease, length of follow-up, and treatment with auto-BMT, there were no statistically significant associations between the development of clonal chromosomal abnormalities and age, number of chemotherapeutic regimens, prior local radiation, BMT conditioning regimen (with or without total body irradiation), or type of lymphoma. These studies show that the risk of developing clonal cytogenetic changes after auto-BMT for malignant lymphoma is approximately 9% at 3 years, even when pre-BMT karyotypic studies are normal. The exact significance of these cytogenetic abnormalities in the absence of MDS or AML is unclear.</jats:p

Allogeneic bone marrow transplantation for high-risk acute lymphoblastic leukemia during first complete remission

Abstract Fifty-three patients with high-risk acute lymphoblastic leukemia (ALL) under age 50 with a histocompatible sibling donor received high-dose radiochemotherapy followed by allogeneic bone marrow transplantation (BMT). The high-risk factors used to identify the patients were: white blood cell count at initial presentation, cytogenetic abnormalities, age, extramedullary leukemic infiltration, and time from initial therapy to complete remission. Patients with one or more of the above risk factors who received BMT have a disease-free survival of 61% with a median follow-up of 66 months (range 11 months to 10.6 years), and an actuarial relapse rate of 10%. This study demonstrates that patients with high-risk ALL achieve a significant disease-free survival and cure rate with the use of allogeneic fully matched sibling BMT. However, a properly designed prospective study comparing the outcome of BMT with the best currently available chemotherapy data is required to define the ultimate role of BMT in this group of patients.</jats:p

Total body irradiation and high-dose etoposide: a new preparatory regimen for bone marrow transplantation in patients with advanced hematologic malignancies [published erratum appears in Blood 1987 Jun;69(6):1789]

Abstract In a phase I/II study, 47 patients (median age, 24 years) with hematologic malignancies (33 patients with acute leukemia not in first remission and 14 patients with other advanced malignant hematologic disorders) were treated with total body irradiation and high doses of etoposide (VP16–213) followed by bone marrow transplantation. At the time of analysis, 21 patients were alive, and 19 of them were in continued complete remission for 101 days to greater than 40 months (median, 12 months). The actuarial disease-free survival rate of the 33 acute leukemia patients is 43% (2 SEM, 18%) and the actuarial relapse rate is 32% (2 SEM, 20%). Five of the 14 patients with the other hematologic malignancies are alive, and four of them continue to be free of disease for 8 to 27 months. Pharmacokinetic studies established a strong correlation between the administered drug doses and their plasma levels and also demonstrated complete drug clearance prior to marrow grafting. An etoposide dose of 60 mg/kg body weight was found to be the maximum tolerated dose. This new preparatory regimen was well tolerated and was not associated with specific acute or long-term regimen-related toxicities. Our data suggest that total body irradiation with high-dose etoposide presents a viable alternative to other preparatory regimens. The role of this novel combination remains to be defined by future prospective randomized trials.</jats:p

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

Abstract We report the treatment outcome of allogeneic bone marrow transplantation in ten patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. Six patients are alive and well for 6 to 30 months (median 19 months) after transplantation. Four patients died with transplant related complications. In view of the poor prognosis associated with this disease, marrow ablation followed by allogeneic or syngeneic marrow grafting may be the preferred treatment modality if a suitable marrow donor is available.</jats:p

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

We report the treatment outcome of allogeneic bone marrow transplantation in ten patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. Six patients are alive and well for 6 to 30 months (median 19 months) after transplantation. Four patients died with transplant related complications. In view of the poor prognosis associated with this disease, marrow ablation followed by allogeneic or syngeneic marrow grafting may be the preferred treatment modality if a suitable marrow donor is available.</jats:p

Fractionated total-body irradiation and high-dose etoposide as a preparatory regimen for bone marrow transplantation for 94 patients with chronic myelogenous leukemia in chronic phase

Ninety-four consecutive patients with chronic myelogenous leukemia in first clinical chronic phase, median age of 34.0 years (range, 6.8 to 52.4 years), with a histocompatible sibling donor, were treated with fractionated total body irradiation (1,320 cGy) and high-dose etoposide (60 mg/kg) followed by allogeneic bone marrow transplantation (BMT). The median time from diagnosis to BMT was 7.0 months (range, 2.3 to 72.0 months). Sixty patients were treated before BMT with hydroxyurea alone, four patients with busulfan alone, one patient with interferon alone, and the other 29 patients were treated with various combinations of these drugs. Cumulative probabilities of overall survival, event- free survival, and relapse at 5 years were 73%, 64%, and 14%, respectively. The median follow-up time for surviving patients was 38 months, ranging from 12 to 88 months. By stepwise Cox regression analysis, significant prognostic variables were age at transplant, acute graft-versus-host disease &gt; or = grade II, cytomegalovirus- associated interstitial pneumonitis, and years from diagnosis to BMT.</jats:p

Fractionated total body irradiation and high-dose etoposide as a preparatory regimen for bone marrow transplantation for 99 patients with acute leukemia in first complete remission

Ninety-nine consecutive patients with acute leukemia in first complete remission under age 50 (median age 27 years; age range 1 to 47 years) with a histocompatible sibling donor were treated with fractionated total body irradiation (1,320 cGy) and high-dose etoposide (60 mg/kg) followed by allogeneic bone marrow transplantation. Sixty-one patients were diagnosed with acute myelogenous leukemia (AML), 34 patients with acute lymphoblastic leukemia (ALL), 3 patients with biphenotypic acute leukemia, and 1 patient with acute undifferentiated leukemia. Thirty of the 34 patients with ALL had at least one of the following high-risk factors: age greater than 30, white blood cell count at presentation &gt; 25,000/microL, extramedullary disease, certain chromosomal translocations, or the need for greater than 4 weeks of induction chemotherapy to achieve first complete remission. Cumulative probabilities of disease-free survival and relapse at 3 years were 61% and 12%, respectively, for the 61 patients with AML and 64% and 12%, respectively, for the 34 patients with ALL. By stepwise Cox regression analysis, significant prognostic variables for patients with acute myelogenous leukemia were the presence of acute graft-versus-host disease and increasing age, whereas for patients with acute lymphoblastic leukemia, significant variables were age and the development of cytomegalovirus-associated interstitial pneumonia. Complications related to graft-versus-host disease and relapse of leukemia were the major causes of death.</jats:p