Results of minimally toxic nonmyeloablative transplantation in patients with sickle cell anemia and β-thalassemia

AbstractWe describe previously transfused patients with sickle cell disease (n = 6) and thalassemia (n = 1) who received nonmyeloablative hematopoietic stem cell transplantation (HCT) to induce stable (full or partial) donor engraftment. Patients were 3 to 20 years (median, 9 years) old. All 7 received pretransplantation fludarabine and 200 cGy of total body irradiation; 2 patients also received horse antithymocyte globulin. Patients received bone marrow (n = 6) or peripheral blood stem cells (n = 1) from HLA-identical siblings, followed by a combination of mycophenolate mofetil and cyclosporine or tacrolimus for postgrafting immunosuppression. After nonmyeloablative HCT, absolute neutrophil counts were <0.5 × 109/L and <0.2 × 109/L for a median of 5 days (range, 0–13 days) and 0 days (range 0–13 days), respectively. A median of 0 (range, 0–9) platelet transfusions were administered. No grade IV nonhematologic toxicities were observed. One patient experienced grade II acute graft-versus-host disease. Two months after transplantation, 6 of 7 patients had evidence of donor chimerism (range, 25%–85%). Independent of red blood cell transfusions, these 6 patients initially had increased total hemoglobin and hemoglobin A concentrations and a reduction of reticulocytosis and transfusion requirements. There were no complications attributable to sickle cell disease during the interval of transient mixed chimerism. However, after posttransplantation immunosuppression was tapered, there was loss of the donor graft, and all patients experienced autologous hematopoietic recovery and disease recurrence. One patient did not engraft. The duration of transient mixed chimerism ranged from 97 to 441 days after transplantation in patients 4 and 6, respectively, and persisted until immunosuppressive drugs were discontinued after transplantation. In summary, the nonmyeloablative HCT regimens described here produced minimal toxicity and resulted in transient donor engraftment in 6 of 7 patients with hemoglobinopathies. Although complications from the underlying hemoglobinopathies did not occur during the period of mixed chimerism, these results suggest that stable (full or partial) donor engraftment after nonmyeloablative HCT is more difficult to achieve among immunocompetent pediatric patients with hemoglobinopathies than among adults with hematologic malignancies, perhaps in part because recipients may have been sensitized to minor histocompatibility antigens of their donor by preceding blood transfusions

A Phase I/II Study of Chemotherapy Followed by Donor Lymphocyte Infusion plus Interleukin-2 for Relapsed Acute Leukemia after Allogeneic Hematopoietic Cell Transplantation

The efficacy of donor lymphocyte infusion (DLI) for treatment of relapsed acute leukemia after allogeneic hematopoietic cell transplantation is limited. We hypothesized that interleukin-2 (IL-2) combined with DLI after chemotherapy might augment graft-versus-leukemia effects. To identify a safe and effective IL-2 regimen, a phase I/II study of DLI plus IL-2 therapy was performed for such patients. After chemotherapy, 17 patients received DLI (1 × 108 CD3/kg for patients with related donors, and 0.1 × 108 CD3/kg for those with unrelated donors) and an escalating dose of induction IL-2 (1.0, 2.0, or 3.0 × 106 IU/m2/day representing levels I [n = 7], Ia [n = 9], and II [n = 1]) for 5 days followed by maintenance (1.0 × 106 IU/m2/day) for 10 days as a continuous intravenous infusion. Unacceptable IL-2–related toxicities developed in 1 patient at level I, 2 at level Ia, and 1 at level II. Grades III-IV acute graft-versus-host disease (aGVHD) developed in 5 patients, and extensive chronic GVHD (cGVHD) developed in 8. Eight patients had a complete remission after chemotherapy prior to DLI, and 2 additional patients had a complete remission after DLI plus IL-2 therapy. In conclusion, the maximal tolerated induction dose of IL-2 combined with DLI appears to be 1.0 × 106 IU/m2/day. IL-2 administration after DLI might increase the incidence of cGVHD

Hematopoietic Cell Transplantation as Curative Therapy for Idiopathic Myelofibrosis, Advanced Polycythemia Vera, and Essential Thrombocythemia

AbstractA total of 104 patients, aged 18 to 70 years, with a diagnosis of chronic idiopathic myelofibrosis (CIMF), polycythemia vera (PV), or essential thrombocythemia (ET) with marrow fibrosis were transplanted from allogeneic (56 related and 45 unrelated) or syngeneic (n = 3) donors. Busulfan (BU) or total body irradiation (TBI)-based myeloablative conditioning regimens were used in 95 patients, and a nonmyeloablative regimen of fludarabine plus TBI was used in 9 patients. The source of stem cells was bone marrow in 43 patients and peripheral blood in 61 patients. A total of 63 patients were alive at a follow-up of 1.3–15.2 years (median, 5.3 years), for an estimated 7-year actuarial survival rate of 61%. Eleven patients had recurrent/persistent disease, of whom 8 died. Nonrelapse mortality was 34% at 5 years. Patients conditioned with targeted BU (plasma levels 800–900 ng/mL) plus cyclophosphamide (tBUCY) had a higher probability of survival (68%) than other patients. Dupriez score, platelet count, patient age, and comorbidity score were statistically significantly associated with mortality in univariate models. In a multivariable regression model, use of tBUCY (P = .03), high platelet count at transplantation (P = .01 for PV/ET; P = .39 for other diagnoses), younger patient age (P = .04), and decreased comorbidity score (P = .03) remained statistically significant for improved survival. Our findings show that hematopoietic cell transplantation offers potentially curative treatment for patients with ICMF, PV, or ET

ROLE OF COMORBIDITIES IN OPTIMIZING DECISION-MAKING FOR ALLOGENEIC HEMATOPOIETIC CELL TRANSPLANTATION

&lt;p class="MsoNormal" style="margin: 0cm 0cm 0pt; line-height: 200%;"&gt;&lt;span style="font-size: small;"&gt;&lt;span style="font-family: Times New Roman;"&gt;&lt;span lang="EN-US"&gt;Allogeneic conventional hematopoietic cell transplantation (HCT) following high-dose, myeloablative conditioning regimens has been used since the 1970’s as potentially curative treatment for &lt;/span&gt;&lt;span style="line-height: 200%; mso-bidi-font-size: 11.0pt; mso-bidi-font-family: Arial;" lang="EN-US"&gt;patients with malignant, hematological disorders&lt;/span&gt;&lt;span lang="EN-US"&gt;. &lt;/span&gt;&lt;span style="line-height: 200%; mso-bidi-font-size: 11.0pt; mso-bidi-font-family: Arial;" lang="EN-US"&gt;The toxicities of conditioning regimens have limited conventional HCT to relatively young patients in otherwise good medical condition.&lt;/span&gt;&lt;span lang="EN-US"&gt; &lt;/span&gt;&lt;span style="line-height: 200%; mso-bidi-font-size: 11.0pt; mso-bidi-font-family: Arial;" lang="EN-US"&gt;With the development of less toxic nonmyeloablative regimens and improvements in supportive care, increasing numbers of older and medically infirm patients have been treated by allogeneic HCT. &lt;/span&gt;&lt;span lang="EN-US"&gt;Until recently, there has been almost no effort to evaluate the prevalence of comorbidities among HCT recipients and their impact on outcomes. We first evaluated the Charlson Comorbidity Index (CCI) developed for patients with solid malignancies, for this purpose. While useful, it lacked sensitivity and specificity for the HCT setting. We next introduced the HCT-specific comorbidity index (HCT-CI) which was based on objective laboratory data to better define comorbidities. Here, we describe this development and illustrate the usefulness of the HCT-CI in predicting HCT outcomes in patients with myeloid and lymphoid malignancies undergoing allogeneic transplantation&lt;/span&gt;&lt;/span&gt;&lt;/span&gt;&lt;/p&gt;&lt;p class="MsoNormal" style="margin: 0cm 0cm 0pt; line-height: 200%;"&gt;&lt;span lang="EN-US"&gt;&lt;span style="font-size: small; font-family: Times New Roman;"&gt; &lt;/span&gt;&lt;/span&gt;&lt;/p&gt

MEDITERRANEAN JOURNAL OF HEMATOLOGY AND INFECTIOUS DISEASES www.mjhid.org ISSN 2035-3006 Original Article Role of Comorbidities in Optimizing Decision-Making Making for Allogeneic

which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited Allogeneic conventional hematopoietic cell transplantation (HCT) following high high-dose, myeloablative conditioning regimens has been used since the 1970’s as potentially curative treatment for patients with malignant, hematological disorders. The toxicities of conditioning regimens have limited conventional HCT to relatively young patients in otherwise good medical condition. With the development of less toxic nonmyeloablative ablative regimens and improvements in supportive care, increasing numbers of older and medically infirm patients have been treated by allogeneic HCT. Until recently, there has been almost no effort to evaluate the prevalence of comorbidities among HCT recipients and their impact on outcomes. We first evaluated the Charlson Comorbidity Index (CCI) developed for patients with solid malignancies, for this purpose. While useful, it lacked sensitivity and specificity for the HCT setting. We next introduced the HCT-specific specific comorbidity index (HCT-CI) which was based on objective laboratory data to better define comorbidities. Here, we describe this development and illustrate the usefulness of the HCT-CI CI in predicting HCT outcomes i