Incomplete Engraftment Research Articles

Preclinical studies of efficacy thresholds and tolerability of a clinically ready lentiviral vector for pyruvate kinase deficiency treatment

Pyruvate kinase deficiency (PKD) is a rare autosomal recessive disorder caused by mutations in the PKLR gene. PKD is characterized by non-spherocytic hemolytic anemia of variable severity and may be fatal in some cases during early childhood. Although not considered the standard of care, allogeneic stem cell transplantation has been shown as a potentially curative treatment, limited by donor availability, toxicity, and incomplete engraftment. Preclinical studies were conducted to define conditions to enable consistent therapeutic reversal, which were based on our previous data on lentiviral gene therapy for PKD. Improvement of erythroid parameters was identified by the presence of 20%–30% healthy donor cells. A minimum vector copy number (VCN) of 0.2−0.3 was required to correct PKD when corrected cells were transplanted in a mouse model for PKD. Biodistribution and pharmacokinetics studies, with the aim of conducting a global gene therapy clinical trial for PKD patients (RP-L301-0119), demonstrated that genetically corrected cells do not confer additional side effects. Moreover, a clinically compatible transduction protocol with mobilized peripheral blood CD34+ cells was optimized, thus facilitating the efficient transduction on human cells capable of repopulating the hematopoiesis of immunodeficient mice. We established conditions for a curative lentiviral vector gene therapy protocol for PKD.

Sequential Therapy for Patients with Primary Refractory AML — a Retrospective Analysis of the German and Israeli Experience

Introduction -primary refractory AML is associated with a dismal prognosis with only 30% of the patients responding to salvage chemotherapy and continuing to allogeneic hematopoietic cell transplantation (HCT). HCT with a standard myeloablative conditioning regimen ,given to patients with a primary refractory leukemia,is associated with 10-20% long- term overall survival. The fludarabine, amsacrine, and cytarabine (FLAMSA)-reduced-intensity conditioning (TBI-based or treosulfan-based) protocol, established by the German group, has been described to be effective approach in patients with relapse/refractory AML undergoing HCT. Modified protocol (without amsacrine and with TBI-based RIC, FITCy) has been also used in the last several years.Methods - We retrospectively analyzed the HCT characteristics and outcomes of all consecutive patients ,diagnosed with primary refractory AML who underwent HCT with either the FLAMSA or FITCy regimens in the University of Cologne and the Tel Aviv Medical Center. Patients who underwent sequential therapy for relapsed disease (either chemosensitive or refractory) were excluded from this analysis.Results - Between the years 2003 and 2017, we identified 43 patients that were eligible for this analysis. Median age was 54 (range, 23-73) years (Table). Median follow-up for surviving patients was 32 (range, 1-148) months. Twelve patients (28%) received only one line of chemotherapy (mostly 7+3) before proceeding at a refractory state to HCT. Preparative regimens were FLAMSA-TBI based, FLAMSA-Treo based and FITCy in 12 (28%), 12 (28%), and 19 (46%) patients, respectively. Prior to HCT, 5 (12%) patients had ongoing documented infections (either microbiology or clinically) - aspergilus pneumonia (n=3), atypical pneumonia (n=1), and scrotal abscess (n=1). Median days to engraftment of neutrophils (>500/dL) and to incomplete engraftment of platelets (>20000/dL) were 13 (range, 9-19) days, and 13 (7-30) days, respectively. Only 1 patient (2%) had primary graft rejection. Severe mucositis was observed in only 10% of the patients, and was mostly observed in the upper gut. 3 patients (7%) developed fungal pneumonia and 2 patients (5%) had blood stream infection during the neutropenic period. Only 2 patients (5%) developed sinusoidal obstruction syndrome.Complete remission was documented on day 30, in all but 1 patient. Cumulative incidences of grade 2-4 and 3-4 acute GVHD at day 100 were 40% and 20%, respectively. Cumulative incidences of overall chronic GVHD and moderate-severe chronic GVHD at 1 year after HCT were 76% and 52%, respectively. Cumulative incidences of relapse at 1 year and 2 years post HCT were 22% and 25%, respectively. Non-relapse mortality rates, at 30 days, 100 days and 1 year post HCT were 7%, 10%, and 22%, respectively. Cumulative incidences of 1, 2,and 3 years overall survival were 66%, 60%, and 57% , Figure. Both older age and a mismatched donor were associated with decreased overall survival (HR=0.83, 95% CI=.335-.969, p=.02) and (HR=.25, 95% CI=.064-.954, p=.046), while time from 1st line regimen to HCT, uncontrolled infections at HCT, percentage of BM blasts prior to HCT, and type of the preparative conditioning were not predictive for survival.Conclusions - Sequential therapy in patients with primary refractory AML is safe and provides a remarakablre anti- leukemic effect. In patients with available donors, this strategy may be superior to repeating rounds of salvage chemotherapy and should be further studied in other settings (i.e. haploidentical donors and other diseases). Future protocols should focus on decreasing GVHD rate , maintaining the graft vs. leukemia effect. [Display omitted] DisclosuresScheid:BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Takeda: Consultancy, Honoraria.

Recent Advancements and Applications of Human Immune System Mice in Preclinical Immuno-Oncology.

Significant advances in immunotherapies have resulted in the increasing need of predictive preclinical models to improve immunotherapeutic drug development, treatment combination, and to prevent or minimize toxicity in clinical trials. Immunodeficient mice reconstituted with human immune system (HIS), termed humanized mice or HIS mice, permit detailed analysis of human immune biology, development, and function. Although this model constitutes a great translational model, some aspects need to be improved as the incomplete engraftment of immune cells, graft versus host disease and the lack of human cytokines and growth factors. In this review, we discuss current HIS platforms, their pathology, and recent advances in their development to improve the quality of human immune cell reconstitution. We also highlight new technologies that can be used to better understand these models and how improved characterization is needed for their application in immuno-oncology safety, efficacy, and new modalities therapy development.

Bone Marrow Transplantation after Nonmyeloablative Treosulfan Conditioning Is Curative in a Murine Model of Sickle Cell Disease

Allogeneic hematopoietic stem cell transplantation (HSCT) can be curative for patients with sickle cell disease (SCD). However, morbidity associated with myeloablative conditioning and graft-versus-host disease has limited its utility. To this end, autologous HSCT for SCD using lentiviral gene-modified bone marrow (BM) or peripheral blood stem cells has been undertaken, although toxicities of fully ablative conditioning with busulfan and incomplete engraftment have been encountered. Treosulfan, a busulfan analog with a low extramedullary toxicity profile, has been used successfully as part of a myeloablative conditioning regimen in the allogeneic setting in SCD. To further minimize toxicity of conditioning, noncytotoxic monoclonal antibodies that clear stem cells from the marrow niche, such as anti-c-Kit (ACK2), have been considered. Using a murine model of SCD, we sought to determine whether nonmyeloablative conditioning followed by transplantation with syngeneic BM cells could ameliorate the disease phenotype. Treosulfan and ACK2, in a dose-dependent manner, decreased BM cellularity and induced cytopenia in SCD mice. Conditioning with treosulfan alone at nonmyeloablative dosing (3.6 g/kg), followed by transplantation with syngeneic BM donor cells, permitted long-term mixed-donor chimerism. Level of chimerism correlated with improvement in hematologic parameters, normalization of urine osmolality, and improvement in liver and spleen pathology. Addition of ACK2 to treosulfan conditioning did not enhance engraftment. Our data suggests that pretransplant conditioning with treosulfan alone may allow sufficient erythroid engraftment to reverse manifestations of SCD, with clinical application as a preparative regimen in SCD patients undergoing gene-modified autologous HSCT.

Posttransplant Intramuscular Injection of PLX-R18 Mesenchymal-Like Adherent Stromal Cells Improves Human Hematopoietic Engraftment in A Murine Transplant Model.

Late-term complications of hematopoietic cell transplantation (HCT) are numerous and include incomplete engraftment. One possible mechanism of incomplete engraftment after HCT is cytokine-mediated suppression or dysfunction of the bone marrow microenvironment. Mesenchymal stromal cells (MSCs) elaborate cytokines that nurture or stimulate the marrow microenvironment by several mechanisms. We hypothesize that the administration of exogenous MSCs may modulate the bone marrow milieu and improve peripheral blood count recovery in the setting of incomplete engraftment. In the current study, we demonstrated that posttransplant intramuscular administration of human placental derived mesenchymal-like adherent stromal cells [PLacental eXpanded (PLX)-R18] harvested from a three-dimensional in vitro culture system improved posttransplant engraftment of human immune compartment in an immune-deficient murine transplantation model. As measured by the percentage of CD45+ cell recovery, we observed improvement in the peripheral blood counts at weeks 6 (8.4 vs. 24.1%, p < 0.001) and 8 (7.3 vs. 13.1%, p < 0.05) and in the bone marrow at week 8 (28 vs. 40.0%, p < 0.01) in the PLX-R18 cohort. As measured by percentage of CD19+ cell recovery, there was improvement at weeks 6 (12.6 vs. 3.8%) and 8 (10.1 vs. 4.1%). These results suggest that PLX-R18 may have a therapeutic role in improving incomplete engraftment after HCT.

Mitigating effects of hUCB-MSCs on the hematopoietic syndrome resulting from total body irradiation

This study evaluated the clinical and pathologic effects of human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) in the recovery from total body irradiation by comparing it with the effects of granulocyte-colony stimulating factor (G-CSF), an efficacious drug in the treatment of acute bone marrow radiation syndrome. BALB/c mice were treated with G-CSF or hUCB-MSCs after they were irradiated with 7 Gy cobalt-60 γ-rays. Circulating blood counts, histopathologic changes in the bone marrow, and plasma level of Flt-3L and transforming growth factor (TGF-β1) were monitored in the postirradiation period. Hematologic analysis revealed that the peripheral leukocyte counts were markedly increased in the hUCB-MSCs-treated group, whereas G-CSF-treated mice did not recover significantly. Moreover, differential counts showed that hUCB-MSC treatment has regenerative effects on white blood cells, lymphocytes, and monocytes compared with the irradiated group. Treatment with hUCB-MSCs or G-CSF significantly increased immunoreactivity of Ki-67 until 3 weeks after total body irradiation. However, at 3 weeks, the number of Ki-67 immunoreactive cells significantly increased in the hUCB-MSCs-treated group compared with the G-CSF-treated group. Furthermore, hUCB-MSC treatment significantly modulated plasma levels of the hematopoietic cytokines Flt-3L and TGF-β1, whereas G-CSF treatment failed to decrease the plasma Flt-3L levels at 2 weeks after irradiation. Based on the differences in circulating blood cell reconstitution and cell density of bone marrow, the authors suggest that MSC treatment is superior to G-CSF treatment for hematopoietic reconstitution following sublethal dose radiation exposure.

G-CSF mobilized vs conventional donor lymphocytes for therapy of relapse or incomplete engraftment after allogeneic hematopoietic transplantation

There is little data comparing the activity and toxicity of donor lymphocyte therapy with granulocyte (G)-CSF-mobilized cells (G-donor lymphocyte infusion (DLI)) with the conventionally collected DLI (C-DLI) after allogeneic blood or marrow transplantation. We retrospectively evaluated 67 patients to compare the efficacy and toxicity of GCSF-mobilized DLI with C-DLI in the treatment of relapse of malignant disease or poor donor engraftment post transplant. We assessed clinical outcomes that may represent the immunological outcome of DLI. The median OS was 210 days (range 3-2436 days), 291 days (range 17-1491 days) in the G-DLI group (15 patients) and 207.5 days (range 3-2436 days) in the C-DLI group (52 patients). The median PFS time was 72 days (range 8-1491 days) in the G-DLI group vs 82 days (range 1-2436 days) in the C-DLI group. Rates of post DLI GVHD and improvement in donor engraftment were similar in the G-DLI and C-DLI groups. We conclude that G-DLI appears to have similar therapeutic activity to that seen with C-DLI, and where such cells are available they may be substituted for conventional donor lymphocytes.

Factors Associated with Peripheral Blood Stem Cell Yield in Volunteer Donors Mobilized with Granulocyte Colony-Stimulating Factors: The Impact of Donor Characteristics and Procedural Settings

Peripheral blood stem cells (PBSCs) are increasingly used as the source of hematopoietic stem cells, but there are large variations in harvest outcome between individuals mobilized by granulocyte colony-stimulating factor (G-CSF). We examined the effects of donor characteristics and procedure factors on the day 1 CD34+ cell yield in 373 unrelated healthy donors. G-CSF was administered subcutaneously at a planned dose of 8.3 to 11 microg/kg daily for 5 days, followed by harvest started on day 5 of G-CSF treatment. Of the 373 donors, 159 (42.6%) had the radial artery as the inlet access for harvest. Poor day 1 cell yield was defined as <10x10(6) CD34+ cells/L of processed blood for the first apheresis; 62 donors (16.6%) did not attain this threshold. The male donors had significantly higher yields at harvest compared with the female donors. The female donors had higher CD34+ cell yields if the circulation access was through an artery than if is was through a vein. In a multiple regression analysis, donor age, sex, body mass index (BMI), preharvest white blood cell and circulating immature cell counts, access type, and flow rate correlated with day 1 yield. Female sex, older age, venous access, and a higher flow rate were significantly associated with greater risk for a day 1 poor yield of CD34+ cells (odds ratio=3.0074, 1.045, 4.3362, and 1.1131, respectively). A higher BMI may decrease the risk (odds ratio=0.8472). In donors at higher risk for poor CD34+ cell yield, strategies for increasing CD34+ cells must be considered.

Infusion of allogeneic-related HLA mismatched mesenchymal stem cells for the treatment of incomplete engraftment following autologous haematopoietic stem cell transplantation

Infusion of allogeneic-related HLA mismatched mesenchymal stem cells for the treatment of incomplete engraftment following autologous haematopoietic stem cell transplantation

Favorable Impact of T Cell Depleted PBSCT on Transplant Outcomes Despite Delayed Donor T Cell Engraftment.

Although T cell depleted stem cell transplantation can reduce risks from GVHD, it is associated with incomplete engraftment and higher relapse rates. To mitigate these negative effects we evaluated a T cell depleted PBSCT protocol followed by delayed add-back of donor T cells. Between 2001–2004, 56 patients with hematological malignancies received a preparative regimen of total body irradiation 12Gy, fludarabine 125mg/m2, and cyclophosphamide 120mg/kg followed by a T cell depleted PBSCT from an HLA identical sibling. The T cell dose was adjusted to 2 x 104/kg in all patients. Patients not developing grade <II GVHD received 107CD3 cells/kg between days 45–100. Lineage-specific T cell and myeloid chimerism was monitored day 14, 30, 45, 60 and 90 post-transplant. Patients were aged between 11–56 (median 30y). Twenty six with CML in CP, acute leukemia in first remission, or MDS RA were designated as standard risk (SR) for transplant outcome. Thirty with more advanced or refractory disease were designated high risk (HR). Overall survival was 65±7% at a median of 1 year. Disease risk was the major factor affecting outcome with lower relapse and transplant-related mortality (TRM) and higher disease-free survival (DFS) in SR versus HR patients (3.5±3.5 vs. 42±11%, 7.5±4 vs. 17.5±8% and 85±7 vs 36±9% respectively, p< 0.0001). One patient rejected the transplant and died following two further transplant attempts. The remaining patients achieved rapid 100% donor myeloid engraftment, sustained unless relapse occurred. Donor T cell engraftment was incomplete. 0nly 12.5% of patients had full donor T cell chimerism (>95% donor T cells) on day 14, rising to 50% of patients by day 90, with persistent mixed chimerism in some patients beyond 6 months. Predictably, acute GVHD grade I–IV by d60 was significantly correlated with full T cell chimerism (p< 0.0001). There was no significant difference in day 30 lymphocyte count, CMV reactivation or transplant CD34 dose between fully or partially T cell chimeric recipients at any time point. Full T cell chimerism was significantly more frequent in HR vs SR patients (on day 90: 82 vs 24%, p= 0.002). Kaplan-Meier outcome estimates for mixed vs full T cell chimerism were therefore analyzed separately for SR and HR patients. All outcomes (relapse, TRM and DFS) were more favorable (but not significantly so) for patients who had mixed chimerism at any time point between d14–90: of 13 evaluable HR patients fully chimeric at d30 there was a 74% probability of relapse vs a 58% relapse for15 mixed chimeric patients (p=NS). No patient with SR disease relapsed. There was a non-significant DFS advantage for d30 mixed vs full chimeric patients: 95% vs 85%, and 40% vs 20% for SR and HR patients respectively. These results indicate 1) full T cell chimerism is more frequent in HR patients (who have received large cumulative doses of prior chemotherapy) 2) T cell depleted PBSCT have a high frequency of prolonged mixed T cell chimerism. This does not predispose to late graft rejection, is favorable for reducing GVHD and does not negatively affect CMV reactivation, relapse, TRM and DFS.

Sirolimus and tacrolimus allow engraftment of haploidentical and other alternative donor stem cells after non-myeloablative conditioning

Sirolimus (Rapamycin) was added to an established non-myeloablative regimen in order to examine its effects on engraftment and GVHD. Between 5/2001 and 7/2003 32 patients with advanced hematological malignancies received alternative donor hematopoietic cell transplantation. Ages ranged from 22–72 (median 62), and prior therapies from 1–6 (median 3). All received cyclophosphamide 1 gram/M2 days -7 and -6, and fludarabine 25 mg/M2 days -7 through -3 (5 doses). Sirolimus began on day -7 and tacrolimus on day -4, with methotrexate 5 mg/M2 days 1, 3, and 6 after stem cell infusion. Graft sources included haploidentical related donors (3 or 4/6 antigen matched-haplo)-11 cases, 5/6 matched related donors-8 cases, matched unrelated donors (URD) 12 cases, and in one case cord blood. Patients receiving haplo stem cells also received anti-thymocyte globulin 30 mg/M2 days -1, 1, 3, and 6. Engraftment was assessed by whole blood RFLP analysis or XY FISH (sex mismatched transplants). 30/32 patients, including all 11 haplo-stem cell recipients and all 12 unrelated donor recipients, engrafted stably. Only transient, incomplete engraftment was seen in the cord blood recipient and one 5/6 matched recipient. Engraftment was >90% donor in 19/32 (59%) by day 30 and in 20 of 25 (80%) evaluable patients by day 100. 3/5 patients with suboptimal engraftment at day 100 had residual circulating CLL cells. Significant renal dysfunction (creatinine >2.5mg/dl) occurred in 15/32 by Day 100 with 2 patients needing dialysis. Renal failure resolved or abated greatly when tacrolimus was reduced or discontinued. Day 100 transplant related mortality was 3/11 (36%) in haplo-transplant patients and 1/20 (5%) of URD or 5/6 (low risk) transplant patients. Acute GVHD (<D100) was seen in 21 of 32 patients (66%), but was in general easily managed with steroids, particularly after low risk transplants. Day 100 transplant related mortality was 3 of 11 haplo recipients and 1 of 19 low risk patients. In total 20/32 patients survive at a median 209 days post-transplant. 14 of these 20 patients have been free of progression of malignancy since transplant and one more has been disease free for 16 months since chemotherapy and donor lymphocyte infusion (ie. 47% currently progression free). Sirolimus added to tacrolimus and methotrexate appears to facilitate engraftment, minimize graft versus host disease, and potentially contribute to control of malignant disease.

Reticular dysgenesis: HLA non-identical bone marrow transplants in a series of 10 patients.

Reticular dysgenesis is a very rare congenital immunodeficiency classified within the severe combined immunodeficiencies (SCID) and characterized by impairment of both lymphoid and myeloid cell development. We report our experience in 10 patients with RD, treated between 1979 and 1999 with HLA-haploidentical hematopoietic stem cell transplantation (HSCT). All children but one were symptomatic within the first days of their lives. Five patients required two HSCT. Five patients received conditioning therapy with busulfan (16 mg/kg) and cyclophosphamide. Three of them are alive and well with myeloid and T and B cell lymphoid reconstitution, whereas two patients died (one chronic graft-versus-host disease, one pneumonitis). Transplantation without or with other conditioning regimens in the other five cases led to absent or incomplete engraftment and none of these cases survived. These results demonstrate the mandatory need for intensive conditioning before haploidentical HSCT in RD to achieve full lymphoid and myeloid engraftment.

Allogeneic Peripheral Blood Stem-Cell Transfusion for a Case of Incomplete Engraftment after Allogeneic Bone Marrow Transplantation

Allogeneic Peripheral Blood Stem-Cell Transfusion for a Case of Incomplete Engraftment after Allogeneic Bone Marrow Transplantation

Feasibility of peripheral blood stem cell (PBSC) and peripheral blood mononuclear cell (PBMNC) separation in children with a body weight below 20 KG.

Nine children from 10 to 76 months (median 28.0), weighing 8.5 to 19.7 kg (median 13.0 kg) underwent peripheral blood stem cell separation (PBSCS) or peripheral blood mononuclear cell separation (PBMNCS), after insertion of a double-lumen central venous catheter (8-10 French). Separations were performed with a continuous flow blood separator (Fen-wall CS 3000 plus), running a specially adopted separation-program. In 7 children (5 with neuroblastoma IV, 1 with multifocal Ewing's sarcoma, and 1 with rhabdomyosarcoma IV), stem cells were mobilized by application of G-CSF at a dosage of 15-27.7 micrograms/kg body weight (median 16.25) subcutaneously following high-dose chemotherapy, according to the disease-related protocols, whereas 2 children had PBMNCS to induce graft vs. leukemia (GvL)-reaction in the HLA-identical sibling suffering from relapsed chronic myelogenous leukemia (CML: n = 1), or chronic myelomonocytic leukemia (CMML: n = 1) after allogeneic BMT. In all cases, the collecting procedure was performed after filling the cell separator with priming solution consisting of 2 U of irradiated and washed packed red cells, 250 ml human albumin, and 0.9% NaCl. In the 7 patients with solid tumors between 0.45 and 62.7 x 10(6) CD-34 positive cells/kg body weight were separated; the patient who had the lowest yield was separated twice after another mobilizing course. Three patients (2 with neuroblastoma IV and 1 with multifocal Ewing's-sarcoma) underwent a double transplantation with 1-3 portions of the collected stem cells within a 5- to 6-week interval. Two children had a rapid engraftment on both peripheral blood stem cell transplantations (PBSCTs). The third child, who had the lowest yield and was separated twice had prompt engraftment at the first PBSCT but delayed and incomplete engraftment at the second PBSCT. One patient after adoptive immunotransfer with PBMNCs for relapsed CML is now 40 months in complete cytogenetic and molecular biological remission, whereas the other patient treated for relapsed CMML did not respond to the PBMNC-transfusion. The results indicate that PBSCS and PBMNCS can be performed in children with a body weight below 20 kg.

Unrelated donor bone marrow transplantation for hematological malignancies-current status.

We have explored the efficacy and toxicity of hematopoietic stem cell transplantation from unrelated donors for hematologic malignancies and other disorders. While most marrow donors have been identified through the National Marrow Donor Program in cooperation with many international registries, the recent development of unrelated donor umbilical cord blood (UCB) banks has allowed us to also evaluate this stem cell source. Analysis of the first 211 URD BMT performed at the University of Minnesota shows an overall survival of 33%, with older recipient age and transplant from a donor with a major HLA-A or B mismatch independently associated with poorer survival. Analysis of engraftment of URD marrow shows increasing risk of delayed or incomplete engraftment with increasing HLA disparity between URD and recipient. GVHD is increased in recipients of URD marrow compared with recipients of related donor marrow. Malignant relapse, however, is less frequent in URD marrow recipients, perhaps due to an increased graft-versus-leukemia effect. Formal assessment shows quality of life in long term URD BMT survivors (beyond 2 years) is excellent, and not different from that seen in sibling marrow recipients. Data from patients receiving unrelated donor UCB transplantation at the University of Minnesota indicate that UCB is an acceptable alternate source of stem cells, at least for young recipients, and may be associated with a reduced incidence of GVHD. Ongoing studies at the University of Minnesota include examination of the applicability of unrelated UCB transplantation to adult recipients, and of the degree of HLA-incompatibility which can be tolerated in UCB transplantation. Studies to identify the optimal GVHD prophylaxis for URD BMT, and to examine the role of class II matching in transplant outcome are in progress.

Relationship of immunodeficiency to lymphoid malignancy

Individuals with either primary or secondary immunodeficiencies are at high risk to develop not only infections but also malignancy (especially of the lymphoid system). The major focus of this paper is on malignancies that develop in immunodeficiency syndromes, particularly malignancies in naturally occurring immunodeficiencies and following bone marrow transplantation (BMT). As of August, 1986, 514 cases of naturally occurring immunodeficiencies have been registered at the Immunodeficiency Cancer Registry. Overall non-Hodgkin's lymphomas predominate in these patients, accounting for 48.6% of all cases. Non-Hodgkin's lymphoma is the predominant malignancy in ataxia-telangiectasia, common variable immunodeficiency, Wiskott-Aldrich syndrome (WAS) and severe combined immunodeficiency (SCID). The histopathology of the lymphomas differs somewhat in each of the disorders. In WAS, large cell "histiocytic" lymphoma predominates, with most cases having the features of B lymphocytes, including pleomorphic immunocytoma and immunoblastic lymphoma. Non-Hodgkin's lymphoma in SCID also generally has B cell features and in some cases multiple copies of Epstein-Barr virus (EBV) genomic DNA have been found in tumor tissue. In contrast to ataxia-telangiectasia, in which non-Hodgkin's lymphoma is also the predominant neoplasm, the morphology and cell marker characteristics are more similar to those seen in nonimmunodeficient children. The lymphomas in ataxia-telangiectasia are very heterogeneous with representation from all the major histologic subtypes. We have found no relationship between the degree of immunodeficiency and the development of malignancy. Immunodeficiency following BMT, as in naturally occurring immunodeficiencies, appears to predispose patients to the development of lymphoid malignancy, especially for recipients of partially mismatched bone marrow. In Minnesota 8 patients have developed B cell lympho-proliferative disorders (BLPD) following BMT.(ABSTRACT TRUNCATED AT 250 WORDS)

Piperazinedione, total body irradiation, and autologous bone marrow transplantation in chronic myelogenous leukemia.

Eleven patients with Philadelphia chromosome (Ph1)-positive chronic myelogenous leukemia (CML) in blast crisis (ten patients) or accelerated disease (one patient) were treated with piperazinedione (PIP) and fractionated total body irradiation (TBI) followed by autologous bone marrow transplantation (ABMT). Three patients were transplanted with marrow from which the Ph1 clone had been eradicated by prior intensive chemotherapy. All patients responded with disappearance of blasts in bone marrow and peripheral blood. Six patients achieved a second chronic phase lasting 3 to 14 months (median, 6 months). Two patients had incomplete recovery, and three patients failed to engraft and died from infection. Transplantation with Ph1-negative bone marrow did not improve response duration or survival. Recurrence of blast crisis and incomplete engraftment continue to be the two major problems in this patient group, and more active regimens need to be investigated.