bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical Results of a −80°C Simplified Cryo-Preservation Method.
Authors: Escoboza Jose R. Borbolla , Lopez-Hernandez Manuel A. , Garza Marcos E. , Baez Enrique , Trueba Elvira , Hernandez Roberto , DeDiego-FloresChapa Jose E. , Baltazar Severiano , Alvarado Martha , Villareal Gerardo , Gonzalez-Avante Mauricio C. , De Leon Rosa E. , Cedillo Jose L. , Penniecook Jason A. , Tovar Yara E. , Leon Maria I. , Ramirez-Assad Cecilia
Published: April 2020

Introduction: Autologus Stem Cell Transplant (ASCT) has found it’s place in the therapy of some common neoplastic diseases such as lymphoma, Hodgkin’s disease and multiple myeloma, and is still under research in a many other malignant and non-malignant diseases such as autoimmune disorders. One common problem for centers performing these procedures in the developing world is the remote possibility of acquiring the controlled-rate freezing and liquid Nitrogen storage apparatus.

Method: We have previously described a simple cryopreservation technique that does not require controlled-rate freezing nor liquid Nitrogen, and only utilizes common hospital equipment (Borbolla, et al. Blood 2000,96;11:1654a).

Results: Our group has performed 35 Autologus stem cell transplants in three different hospitals, using this cryopreservation method. All transplants were performed using peripheral blood stem cells obtained by apheresis. Mean CD34+ cell counts before cryopreservation were 2.72 X10^8 (SD:±1.07). Mean number of days between cryopreservation and transplant was 23.31 (SD:±15.66). Mean cell viability using Trypan blue method was 95%. One heavily treated and irradiated patient had engraftment failure. Mean number of days to neutrophil engraftment (ANC>500 cells/μL) was 14.55 (SD:±4.54); and for platelet engraftment (Plt>20,000/μL) was 23.18 (SD:±6.85).

Conclusion: Our cryopreservation method is comparable to other more expensive and cumbersome variants. Despite the fact that there is controversy surrounding some new indications for ASCT, some indications are already established and increase significantly the possibilities of a great number of patients to be cured from many malignant diseases such as NHL, Hodgkin’s disease, multiple myeloma, germ cell cancers and Ewing’s sarcoma, among others.

While there is no centralized data, the number of ASCT procedures performed in developing countries is known to be staggeringly low. The authors believe that behind these very low numbers, are economic issues and not professional capabilities of our health personnel. With the help of a Humanitarian Service Institution (Rotary International) we are currently working with a hospital in a Caribbean country to help them start performing ASCT using this cryopreservation method. Just as we did in our year 2000 meeting poster, we encourage Hematology departments in developing countries to get in touch with us (borbolla@itesm.mx) in order to arrange for this free technology transfer which will enable them to offer this procedure to their patients.
Nonmyeloablative Hematopoietic Stem Cell Transplantation for the Treatment of Systemic Sclerosis.
Authors: Shiratsuchi Motoaki , Motomura Seiichi , Ikuta Takuya , Ohno Hirofumi , Shiokawa Satoshi , Nishimura Junji
Published: April 2020

Systemic sclerosis (SSc) is an autoimmune disease which is characteristic of diffuse scleroderma and visceral organ fibrosis. Various kinds of therapies including immunosuppressive drugs have been attempted yet all proved ineffective. In order to reconstitute the immune system and cure SSc patients, we started a clinical trial of nonmyeloablative hematopoietic stem cell transplantation (NST) for the treatment of SSc. The inclusion criteria consisted of an age younger than 70 years, SSc as defined by Ministry of Health, Labor, and Welfare, a duration of less than 4 years since the diagnosis of SSc, a skin score of more than 15 points, and moderate organ failure. We herein describe the first patient to take part in this trial. A 52-year-old female suffered from scleroderma and we diagnosed to have SSc in 2000. Although she was treated with prednisolone, cyclophosphamide, penicilamine, and prostagrandin, the scleroderma was progressive (skin score 30 points) and the interstitial pneumonia also worsened (%VC 66.5 %, serum KL-6 level 1080 U/mL). In November 2003, we enrolled her as the first patient to undergo NST after her informed consent was obtained. After conditioning therapy consisting of low dose TBI (200 cGy) and fludarabine (30mg/m2, 3days), G-CSF-mobilized peripheral blood stem cells from an HLA- identical brother were infused.

Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine and mycophenolate mofetil. No blood transfusion was performed. Complete donor chimerism was obtained and has continued since 1 month after NST. The cyclosporine dosage was tapered gradually, and no apparent acute or chronic GVHD was seen. Three months after NST, the patient’s skin score improved to 19 points and a skin biopsy showed mild lymphocyte infiltration. At 8 months after NST, the area of interstitial pneumonia decreased according to the computed tomography findings and the %VC levels and serum KL-6 level were both found to have substantially improved (70.3 % and 746 U/mL, respectively). Although the duration after NST is still short, the clinical course for this patient is presently appears to be promising.
Preliminary Data on Once-Daily IV Busulfan at 3.2 mg/kg/day Indicate That It Is Safe as a Component of the Conditioning Regimen for Hematopoietic Stem Cell Transplantation.
Authors: Brunvand Mark W. , Rifkin Robert , Matous Jeffry V. , McSweeney Peter , Bearman Scott
Published: April 2020

Busulfan is a useful chemotherapy in many stem cell transplant regimens. Data support the use of buslfan in transplant patients, especially if they have had prior treatment with radiation therapy. The dose of the busulfan used in myloablative stem cell transplantation has traditionally been sixteen oral doses of 1mg/kg/dose. The oral dosing has been limited by unreliable oral absorption of busulfan tablets. Transplant related mortality and incidence of venocclusive disease are directly related to high peak levels of busulfan. Relapse has been associated with low peak levels of busulfan.

Recently, busulfan has become available as an IV preparation and preliminary data indicate that the peak busulfan levels are predictable via the IV administration route. The bulk of the data available on outcomes after transplantation using IV busulfan have used a QID dosing schedule of 0.8mg/kg/dose for sixteen doses. A smaller data base has utilized IV busulfan for stem cell transplantation as a single daily dose of 3.2mg/kg/day for 2–4 days. We present data on 19 patients treated at RMBMTP for hematological malignancies with the 3.2mg/kg/day dosing for stem cell transplantation. Sixteen of the 19 patients underwent allogeneic stem cell transplantation from related or unrelated donors from April 2003 to March 2004. Three patients underwent autologous stem cell transplants using the IV busulfan 3.2 mg/kg/day with cyclophosphamide 120 mg/kg total dose. None of the autologous transplant patients developed VOD or death during the first 100 days. 8 of the 16 patients undergoing allogeneic stem cell transplant have died: 4 patients died of relapsed disease, 2 died of GVHD, 1 patient died of sepsis, and 1 died of GVHD, relapse and a fungal infection. No autologous or allogeneic stem cell transplant patients died of regimen related toxicity.

This single daily dose regimen has been well tolerated with no increase in transplant related mortality or VOD. The 3.2 mg/kg/day dose appears adequate to assure engraftment of allogeneic stem cells. The patients presented had high-risk hematological malignancies. Although the followup is short, the OS survival of 100% for the autologous stem cell transplants and 50% for the allogeneic stem cell transplantation is consistent with published data for transplantation of high-risk hematological malignancies. There does not appear to be a higher transplant related mortality, GVHD or VOD rate for patients treated with busulfan at 3.2 mg/kg/day as a single dose.
ABO Incompatible Allogeneic Stem-Cell Transplantation Following Reduced-Intensity Conditioning: Close Association with Thrombotic Microangiopathy.
Authors: Worel Nina , Greinix Hildegard T. , Mitterbauer Margit , Schulenburg Axel , Hoecker Paul , Keil Felix , Kalhs Peter
Published: April 2020

Thrombotic microangiopathy (TM) is a severe complication of stem cell transplantation (SCT) associated with high mortality rates. One of the major risk factors for the development of TM is the toxic effect of high-dose chemo-radiotherapy, heavy pretreatment and the use of unrelated donors (URD) grafts. To reduce transplant related mortality in patients at risk non myeloablative conditioning regimens have been introduced.

We reviewed data on 83 consecutive patients given sibling (n=44) and URD (n=39) SCT after reduced intensity conditioning and graft versus host (GvHD) prophylaxis with CsA and mycophenolate mofetil with respect to occurence of TM. Diagnoses consisted of ALL (n=5), AML (n=31), CML (n=8), MDS (n=6), MM (n=11), NHL (n=17), renal cell cancer (n=4) and n. ovarii (n=1). A group of 565 patients undergoing high-dose conditioning followed by sibling (n=372) an URD (n=193) SCT served as control. The majority of these patients received CsA and MTX as GvHD prophylaxis. The diagnoses of TM was confirmed by renewed thrombocytopenia, coombs negative hemolysis, increased LDH-levels and fragmented red cells in peripheral blood smears. TM occured in 9 of 83 patients (11%) after RIC compared to 25 of 565 patients (4,4%) after high-dose conditioning, respectively. All but one patient in the RIC group received an ABO-incompatible stem cell graft (p< 0.05). The median time of onset of TM was 62 days after SCT (range, 9 to 906 days) in this group. Donor source (sibling/URD) had no influence on the risk of developing TM (p=0.07). TM was associated with severe acute GvHD (n=2), chronic extensive GvHD (n=3), sepsis (proteus mirabilis n=1), herpes virus infection (n=1), severe hemolysis after minor ABO-incompatible SCT (n=1) and computed tomography approven atypical pneumonia (n=1). First line treatment consisted of withdrawal of cyclosporine A and plasmaexchange treatment (median exchange procedures 14, range 8 to 30). Overall, 5of 9 (55%) patients responded, 3 patients died due to GvHD and TM, 1 of multi- organ failure. One patient who responded to plasmaexchange died 1 year later due to relapse.

Posttransplant TM is a common severe complication and seems to increase after reduced-intensity conditioning. Fludarabin, a major constitute of RIC, is not reported to cause TM. How far GvHD-prophylaxis without MTX plays a role in the development of TM remains unclear. Of particular importance is that patients receiving ABO-incompatible stem cell grafts have a significant higher risk to develop TM after allogeneic SCT following reduced-intensity conditioning.
The Impact of Monitoring Epstein Barr Virus PCR in Paediatric Bone Marrow Transplant Patients: Can It Successfully Predict Outcome and Guide Intervention.
Authors: Greenfield Hayley M. , Gharib Maged I. , Turner Andrew J.L. , Coussons Mary L. , Will Andrew M. , Jarrett Ruth F. , Macheta Mario P. , Wynn Robert F.
Published: April 2020

Epstein Barr Virus (EBV) associated Lymphoproliferative Disease (LPD) is a complication of allogeneic haemopoietic stem cell tranplantation (HSCT). In certain groups (congenital immunodeficiency, unrelated and mismatched donor transplants, T cell depletion) the risk may be as high as 25% with significant morbidity and mortality. Strategies to predict such illlness and allow early intervention have therefore assumed importance.

We have routinely screened peripheral blood of paediatric, transplanted patients by quantitiative PCR. We report the results of such analysis of 28 successive patients and the EBV serial quantitation in 4 patients with EBV LPD. The median age at time of transplant was 6.5 years. 17 patients received an unrelated donor transplant and one patient received a haplo-identical transplant. The remainder (n=9) received a matched family donor transplant. 23 patients received either Alemtuzumab (n=19) or ATG (n=4). 13 patients had leukaemia, 5 had mucopolysaccharide syndrome, 4 for congential immune deficiency and 6 for non malignant haeamtological conditions.

9 (32%) patients showed no evidence of EBV reactivation using serial PCR monitoring. 10 patients had low level EBV reactivation as defined with a PCR log[copy number] <4.5 copies/ml. 9 patients had a higher level of EBV reactivation. 2 patients had clinical EBV LPD and 2 additional LPD patients with LPD and with archived serial blood samples were also analysed.

All patients with clinical LPD fell in the high level reactivation group. All patients with high level reactivation had received either Alemtuzumab or ATG. Patients within this high level group with LPD had a higher PCR log value again than those without LPD (all patients with EBV LPD had levels > 6, whilst the highest level without disease was 5.2). All 4 patients responded to therapy for EBV LPD, with a combination of rituximab, withdrawal of immune suppression or administration of donor lymphocytes - DLI). At higher EBV levels the quantitative PCR had increasing positive predictive value for clinical LPD.

We therefore conclude that EBV serial quantitative PCR is useful in discriminating those who will develop LPD from those that will not. Our data suggest that it is possible to use EBV PCR quantitation further to discriminate asymptomatic EBV reactivation that will resolve without therapy from EBV reactivation that will require intervention. This prevents over exposure of patients to treatments (rituximab, DLI, immune suppression withdrawal) with significant associated toxicity (prolonged B cell aplasia, graft versus host disease).
Pseudomembranous Colitis Following Autologous Stem Cell Transplantation.
Authors: Hickey Joanne M. , Tompkins Kirsty A. , Duggan Peter R.
Published: April 2020

Introduction: Diarrhea is a well established cause of morbidity post autologous stem cell transplantation (ASCT), occurring in 50–90% of patients - particularly in the first 20–30 days. Clostridium difficile toxin overproduction is a cause of diarrhea and can lead to serious morbidity and mortality. However, previous studies have demonstrated an incidence of C. difficile toxin positive diarrhea post ASCT of only 4%–7%. Our aims were to retrospectively identify the prevalence of C. difficile positive diarrhea in our population of ASCT patients in the first 30 days post transplant, and to retrospectively identify the prevalence of empiric antibiotic treatment for C. difficile diarrhea in these patients during the same time period.

Methods: All patients who received ASCT or immediate post transplant care at the General Hospital, Health Sciences Centre between April 1996 and March 2004 were identified and the results of any stool cultures sent in the first 30 days post transplant were recorded. In addition, the use of metronidazole during the same time period in any patient with a stool culture sent was identified.

Results: A total of 101 patients received ASCT or post transplant care between April 1996 and March 2004. Of these, 63 patients (62%) had a total of 75 stool cultures sent for culture and sensitivity as well as C. difficile toxin analysis. A total of 3 cultures from 2 patients (2%) were positive for C. difficile toxin. No other bacteria were isolated from stool samples. Of the 63 patients having C. difficile toxin analysis, 30 (48%) were treated with a course of metronidazole.

Conclusions: Our population of ASCT patients have similar rates of C. difficile positive diarrhea as previously studied populations. Despite the very low frequency of C. difficile diarrhea in our patients, there was a high prevalence of empiric antibiotic treatment with metronidazole. Based on this data, we feel that it is safe to forego empiric antibiotic treatment pending stool culture results and to use anti-diarrheal agents to achieve symptomatic relief in patients with diarrhea immediately post ASCT.
Five Years Update Results of Basiliximab (BAMAB) Therapy for Acute Refractory Graft Versus Host Disease (AGVHD).
Authors: Funke Vaneuza A.M. , Bonfim Carmem M. , Bitencourt Marco A. , Setubal Daniela C. , Ruiz Jefferson , Medeiros Carlos R. , Neto Jose Z. , Pasquini Ricardo
Published: April 2020

The IL-2 activation of RAS pathway promotes lymphocyte proliferation, differentiation and development of A-GVHD. This mechanism can be inhibited by basiliximab, a chimeric murin-human monoclonal antibody which binds to the alpha chain of interleukin-2 receptors on activated T-cells. Basiliximab is already largely used to prevent acute rejection after renal transplantation, but the experience with this drug on BMT setting is still limited. We treated 34 patients (pts) with severe refractory A-GVHD with Basiliximab from december 1998 to october, 2003. Median age was 13 years (range: 2 to 38). Most of the patiens had received an unrelated BMT (73%). Cell source was bone marrow in 88% and cord blood in 12% of the patients. Diagnosis included acute leukemia (9 pts), MDS (4 pts), CML(9 pts), Fanconi anemia (9 pts), and SAA (3 pts). Because of a half life of about 7 days, BAMAB schedule was 40mg weekly for 2–3 doses (adults) and 20 weekly for 2–3 doses (children). All pts had a-GVHD grade III-IV, manifesting from day 6–248 after transplant (M: 24 d), while on cyclosporin, and refractory to association with steroids (2–5mg/kg/d). Skin was involved in 32, GI in 25 and liver in 23 patients. Median follow-up was 196 (range: 35–1847) days. Overall response rate was 82% (CR: 11 pts, PR: 17 pts). Two pts (8 %) were not evaluated due to early death. Response varied according to the site involved, being complete in 84% of skin, 48% of GI and 26% of liver GVHD. Duration of response varied from 5–1103 d (M: 38 d). There were no infusion-related reactions. Eleven pts are alive (32%), 7 pts with complete response, 3 with partial response and 1 pt without response. Acute GVHD reactivation was seen on 41% of the patients, but half of them could be rescued with other therapies (MMF, PUVA, steroids). Infection was the main cause of death, being responsible for 83% of all deaths (disseminated CMV-4 pts, fungal infection-6 pts and sepsis-8 pts). Other causes of death included bleeding (2pts) and relapse (2 pts). In conclusion, basiliximab was able to induce response on patients with refractory A-GVHD. Prospective studies with this drug are necessary to address the optimal dose, schedule and incidence of infection.
Comparison of Empiric Versus Prophylactic Administration of Ceftazidime during Neutropenia Associated with Reduced-Intensity Allogeneic Stem Cell Transplantation (RIST).
Authors: Donley Kyle M. , Gea-Banacloche Juan C. , Dean Robert M. , Steinberg Seth M. , Childs Richard W. , Odom Jeanne , Castro Kathleen , Chinn Tracey , Fowler Daniel H. , Bishop Michael R.
Published: April 2020

Broad spectrum antibiotics are sometimes used prophylactically during the neutropenic phase of stem cell transplantation, but this practice is controversial. Possible benefits include the prevention of fever and infectious episodes. Possible disadvantages include increased usage of antibiotics with associated increases in cost, toxicities and development of antibiotic resistance.

OBJECTIVE: To compare prophylactic (PRO) administration of ceftazidime at the beginning of neutropenia (ANC <500) vs. empirical (EMP) initiation of ceftazidime for neutropenic fever in RIST patients during the pre-engraftment period.

METHODS: Retrospective analysis of all patients who received a RIST for hematologic malignancies in two different bone marrow transplant units at the NIH Clinical Center between 2000 and 2003. The PRO group was composed of 41 patients who received prophylactic ceftazidime 2 g iv q 8h when ANC <500. The EMP group was composed of 40 patients who received ceftazidime during neutropenia only if fever developed. Both groups were comparable in terms of baseline disease, age, sex, conditioning regimen (FLU/CY) and gut decontamination. Mean duration of neutropenia was 10.8 days in the PRO group and 13.7 days in the EMP group (p < 0.05), due to differences in GVHD prophylaxis and GCSF usage.

RESULTS: The PRO group presented less episodes of neutropenic fever (16/41, 39% vs. 27/40, 67.5%, p < 0.05), less microbiologically documented infections (4/41, 10% vs 17/40, 43% p < 0.05) and less episodes of bacteremia (1 vs. 7). By Kaplan-Meier analysis the median time to developing fever was significantly longer in the PRO group (9.6 vs 6.8 days p = 0.03). The PRO group received, on average, 5.5 less days of broad-spectrum antibiotics (11.8 vs 17.3). The average number of days on ceftazidime was 10 in the PRO group and 7 in the EMP group. There were no significant toxicities associated with antibiotic use. The susceptibility to ceftazidime on the bacterial isolates from both transplant units did not change significantly between 1999 and 2003, despite the different patterns of antibiotic use.

CONCLUSION: Prophylaxis with ceftazidime may prevent neutropenic fever and microbiologically documented infections during the pre-engraftment phase of RIST, and may result in decreased utilization of broad-spectrum antibiotics.
Reduced Intensity Conditioning Regimen for Allografting Following Cytoreductive Autografting in Metastatic Breast Cancer.
Authors: Carella A.M. , Beltrami Germana , Corsetti Maria T. , Scalzulli Potito , Carella Michele , Gonella Roberta , Ballestreo Alberto , Patrone Franco
Published: April 2020

We postulated that it is possible to safely extend the benefits of allografting to metastatic breast cancer by combining cytoreduction achieved with high-dose therapy and autologous stem cell transplant (HDT/ASCT) and graft versus tumor effect mediated through transplanted donor immune cells with nonmyeloablative allografting (RICT). Seventeen patients, 41 years of age (range, 31–57), with heavily pretreated disease were given HDT/ASCT. No patient died after HDT/ASCT. Thirty-one to 92 days (median, 51 days) after HDT/ASCT the patients received fludarabine 30 mg/m2/day x 3 days and cyclophosphamide 300 mg/m2/day x 3 days and donor PBPC from HLA-identical siblings. Postgrafting immunosuppression consisted of cyclosporine and methotrexate. Donor lymphocyte infusions were given to 11 patients with stable mixed chimerism and/or progressive disease, who did not show signs of GVHD. Thirteen patients (76%) achieved sustained donor engraftment. Three patients achieved partial remission (PR) after HDT/ASCT and complete remission (CR) after RICT; another no-responsive patient achieved PR for an overall response rate of 4/17 (22%). The first signs of responsiveness in CR patients began at day +80, +90 and +110 and the maximal response was achieved on day +240, +300 and +390. The 3 remitters patients achieved full chimerism and developed GVHD before regression of the disease. Grade ≥II aGVHD occurred in 5 patients (29%) and extensive cGVHD in 5 patients (29%). No transplant-related deaths (TRD) were observed during the first 100 days. Three patients died of extensive cGVHD in the first year. At April 2004, 5/17 patients (29%) are alive 90–2160 days (median, 1320) from RICT. In conclusion, this 2-step approach is a feasible procedure in metastatic breast cancer patients; the exploitation of graft versus tumor effect is a promising finding.
Allogeneic Transplantation for Adult Acute Lymphoblastic Leukemia (ALL) with Rituximab or Campath I-H.
Authors: Khouri Issa F. , Saliba Rima M. , Kebriaei Partow , Ma Carrie , Ippoliti Cindy , Couriel Daniel R. , de Lima Marcus , Giralt Sergio , Qazilbash Muzaffar H. , Gajewski James L. , Champlin Richard E.
Published: April 2020

Because of potential synergy with chemotherapy and non-overlapping toxicity, we investigated the addition of Rituximab or Campath 1-H to the standard myeloablative conditioning regimen of cyclophosphamide (60 mg/kg daily x 2) and total body irradiation (12.0 Gy in four fractions) prior to allogeneic transplantation for ALL. Transplantation was performed on day 0. Rituximab was added if patients’ disease expressed CD20+ > 20% by flow-cytometry. It was administered (375 mg/m2 ) on days −6, −1, +7 and +14. Campath I-H (10 mg daily intravenously, days −6 to −2) was added if patients’ CD20 expression was <20% and CD52 >20%. Thirty-two adult consecutive patients were studied. Eleven were in first remission with poor prognostic features, 11 in 2nd remission, and 10 were ≥ 3rd remission, or in relapse. Twenty-nine patients had B-cell, two had T-cell and one had an undifferentiated phenotyping. The study group included 19 males and 13 females of median age 35 yrs (range, 19–57). Median # of prior chemoregimens received was 2 (range, 1–6). In both groups of patients, prophylaxis for GVHD consisted of a combination of tacrolimus and methotrexate. Pharmacokinetic studies in patients who received Campath I-H showed no detectable level of the antibody one-day prior to- or after the infusion of the donor graft. Median follow-up for survivors was 19 months. Outcomes were:

Campath-study group Rituximab-study group P -value Prior Chemoregimens (range) 2(1–6) 2(1–3) 0.04 Donor Type     Matched unrelated 3(28%) 8(38%) 0.2     Matched sibling 7(63%) 12(57%)     Mismatched sibling 1(9%) 1(5%) Cell Source     PB 8(73%) 11(52%) 0.2     Marrow 3(27%) 10(48%) Disease Status     CR1/CR2 5(45%) 17(81%) 0.05     Others 6(55%) 4(19%) Median time ANC >500 13 12 0.07     (range) (11–17) (10–24) Median time Platelets >20K 13 13 0.8     (range) (6 – 31) (7 – 34) Day 100 TRM 0 1(5%) Acute GVHD II–IV (N,% kM) 2 (18%) 5 (24%) 0.7 Acute GVHD III–IV (N, % kM) 0 2 (9%) Chronic extensive GVHD (N, cumulative incidence) 3 (27%) 9 (54%) 0.4 Overall Survival (18 mos) (95% CI) 53% (21 – 77) 52% (26 – 73) 0.9 Disease-free survival (18 mos) (95% CI) 54% (23 – 75) 37% (15 – 60) 0.8

No prognostic factor was found to be of significance for survival, disease-free survival, or relapse. This included: age (<35 vs ≥ 35), source of graft, disease status at transplant, # prior regimens (<2 vs ≥ 2), acute or chronic GVHD, use of Rituximab or Campath. Our results indicate that the addition of Rituximab or Campath I-H in allogeneic transplantation for ALL is safe. There was no delay in engraftment and no added toxicity or risk of mortality. Longer follow-up is needed to evaluate the impact of this strategy upon survival and relapse.
Clinical Status Longer than One Year Post-Transplantation in 4 Recipients of Non-T-Cell-Depleted HLA-Haploidentical Transplantation Based on Feto-Maternal Microchimerism.
Authors: Yoshihara Takao , Morimoto Akira , Kuroda Hiroshi , Ishida Hiroyuki , Imamura Toshihiko , Maruya Etsuko , Saji Hiroh , Imashuku Shinsaku
Published: April 2020

The long-term presence of fetal hematopoietic cells in the maternal blood after childbirth indicates maternal tolerance to fetal inherited paternal antigens (IPA), and also that of maternal hematopoietic cells in the offspring’s blood after birth indicates mutual tolerance to non-inherited maternal antigens (NIMA) among sibling. Based on such recent feto-maternal microchimerism / tolerance theory, more than 40 cases have received non-T-cell-depleted (non-TCD) HLA-haploidentical stem cell transplantation (SCT) for various hematological malignancies in Japan. Their early post-SCT clinical courses have been reported; however, long-term outcome and quality of life of such SCT recipients are largely unknown. In our hospitals, we used non-TCD cells from haploidentical family donors for transplantation in 5 children with hematologic malignancies. Among those children, four have been alive for more than one year. Three of the 4 recipients still require prophylactic immunosuppressants for chronic GVHD. Only one case developed chronic GVHD (skin limited). Various late complications are noted in 3. Three children showed complete school attendance. Two of the three are also allowed to participate in physical exercises. These results suggest that quality of life in long-term survivors in childhood from non-TCD HLA-haploidentical SCT based on feto-maternal microchimerism seems acceptable although the numbers are still small and the follow-up period is short.

Patients characteristics

Case Age Diagnosis Status Donor HLA mismatch acute GVHD Survival after SCT (days) 1 6 ALL CR1 (advanced remission) NIMA-mismatched sibling 2 2 CR, 802+ 2 11 ALL Rejection after UCBT (CR2) Mother 2 1 CR, 775+ 3 16 MLL Refractory relapse after UCBT Mother 2 1 CR, 519+ 4 14 CML Blastic phase Mother 2 1 CR, 473+ 5 6 ALL Rejection after UCBT (Rel 1) Mother 3 2 Dead, 93

Present status of long-term survivors

Case chronic GVHD Karnofsky score Late complications School attendance Physical exercise Medication 1 - 100 - complete permitted - 2 - 100 hypothyroidism complete permitted FK506 3 + (skin) 70 diabetes, esophageal stricture no prohibited PSL+MTX, insulin 4 - 100 arrhythmia complete prohibited FK506
Double-Unit Cord Blood Transplantation in Japan.
Authors: Kai Shunro , Misawa Mahito , Iseki Tohru , Takahashi Satoshi , Kishi Kenji , Hiraoka Akira , Kato Shunnichi , Hara Hiroshi
Published: April 2020

Cord blood (CB) is being increasingly used as a source of hematopoietic stem cells for patients in need of stem cell transplantation when a HLA matched-related or unrelated donor is not found. However, cord blood transplantation (CBT) in adults is limited by its lower cell dose. We have started investigating whether transplant with two units of CB will make an engraftment faster and improve outcomes in adult patient lacking a suitable single CB unit. Four transplant centers have participated in this clinical study. Eligibility for this study are as follows; 1) high-risk or advanced hematological malignancy without a related donor, 2) no HLA-matched unrelated BM donor in JMDP or requirement for urgent transplantation, and 3) absence of single HLA 0–2 antigen-mismatched cord blood unit with a cell dose of >2.5x10e7/kg. Eleven patients with hematological malignancies (AML 7, MLL 2, ALL 1, LBL 1) were transplanted with two CB units, following myeloablative conditioning with fractionated TBI(12Gy)+ G-CSF (5?g/kg/dx2days) combined ara-C (12g/?) +CY (120mg/kg) or TBI(12Gy) + CY (120mg/kg). GVHD prophylaxis consisted of short term MTX and CSA. The median age was 33 years (range; 19–52) and median weight was 68kg (range 48– 84). CB grafts were HLA 0–2 antigen-mismatched to the patients and each other, with a median total cryopreserved cell dose of 3.88x10e7/kg (range; 2.83–4.79) and median CD34+ cell dose of 1.06x10e5/kg (0.62–2.6). Nine out of 11 patients engrafted successfully, and had 96–100% single donor chimerism at day+28 bone marrow aspirate. The median time to neutrophil engraftment (ANC >500 /?) was 21days (16–26) and median time to platelets >50000 /?was 53 days (32–98). Nine patients who survived more than 28 days had AGVHD (grade I in 2, II in 3, III in 1), and CGVHD (limited type) was developed in 4 of the 6 evaluable patients. Two patients died of sepsis at day 7 and 27 and one had relapse at day 249. Nine patients are now alive 3 to 16 months after CBT. These preliminary results suggest that multiple unit CBT seems to be useful for adult with hematological malignancies lacking an appropriate BM donor or a single CB unit. Further studies with double-unit CBT may be warranted.
Comparison of the Feasibility of Adult Allogeneic Umbilical Cord Blood Transplantation between the Myeloablative Conditioning Regimen and the Non Myeloablative One.
Authors: Tashiro Haruko , Kozai Yasuji , Noguchi Mitsuho , Goto Moritaka , Kawasugi Kazuo , Kodo Hideki , Shirafuji Naoki
Published: April 2020

Aim: To make clear the feasibility of non-myeloablative conditioning on the adult allogeneic umbilical cord blood transplantation, we compared the result between patients receiving the myeloablative (conventional) transplantation (CT) and the reduced intensity stem cell transplantation (RIST) in point of the engraftment, and the incidence of GVHD. Patients’

characteristics and Methods: Patients were admitted to our hospitals to receive umbilical cord blood transplantation during May 1999 to May 2004. CT group (n=23): Median age was 33 years. Diagnoses were included AML (n=9), ALL(n=7), NHL(n=4), MDS(n=2), CML(n=1). Preparative conditioning regimens were; TBI/Ara-C/CY (n=16), TBI/VP-16/CY (n=4), TBI/CY (n=3). GVHD prophylaxis was; Cyclosporine A (CsA) (n=11), CsA with short term Methotrexate (MTX) (n=10), Tacrolimus with short term MTX (n=2). The transplanted median cell number was 2.40 x 10^7/kg. HLA disparities were; 1AMM (n=5), 2AMM (n=18), 3AMM (n=3). RIST group (n=13): Median age was 54 years. Diagnoses were; AML (n=3), NHL (n=5), HD (n=2), ATL (n=1), CLL (n=1), CMMoL(n=1). Preparative conditioning regimens were; Flu/ L-PAM (n=4), TBI/ Flu/ L-PAM (n=1), TBI/ Flu/ CY (n=3), TBI/ Flu (n=1), TBI/ Flu/ BU (n=4). GVHD prophylaxis was; CsA (n=5), CsA with MMF (n=7), Tacrolimus (n=1). The transplanted median cell number was 2.49 x 10^7/kg. HLA disparities were; identical (n=3), 1AMM (n=2), 2AMM (n=6), 3AMM (n=2).

Result: The rate of engraftment failure including conditioning failure, and autologous recovery was 14.8 %in CT and 38.1%in RIST, respectively. The median duration of the engraftment of neutrophils in CT and RIST were 24 days and 19 days, respectively. Patients with Grade II-IV acute GVHD were 15 (65.2%) in CT and 8 (61.5%) in RIST, respectively. The incidence of Grade III-IVacute GvHD was 7 ( 30.4%) and 5(38.4%), respectively.

Conclusion: Engraftment in RIST was achieved earlier than CT, however the incidence of engraftment failure was increased in RIST. There were no significant differences on the incidence of acute GVHD between two groups. Further observations, especially long-term disease-free survival are seemed to be very interesting to ascertain RIST on adult umbilical cord blood transplantation.
Reduced Intensity Allografts for Acute Myeloid Leukemia: Defining the Role of Conditioning and Donor Alloreactivity.
Authors: Devine Steven M. , Hallemeier Chris , Fenske Timothy , Vij Ravi , DiPersio John F. , Adkins Douglas A.
Published: April 2020

The role of reduced intensity allografting in the treatment of patients with acute myeloid leukemia (AML) is unclear. While more patients may survive the initial period following allografting in comparison to those receiving full intensity transplants, the risk of relapse may be greater, particularly in patients not in remission at the time of transplantation. Here we report the results of allogeneic transplants using either cytokine mobilized peripheral blood (PB) or bone marrow (BM) following a reduced intensity conditioning (RIC) regimen. 131 patients with AML were all conditioned with an identical regimen containing Cyclophosphamide at 120mg/kg iv over 2 days (days −3 and −2) followed by a single dose of total body irradiation at 550cGy on day −1. HLA-identical (HLA-ID) siblings donated cytokine mobilized PB to 62 recipients and unrelated donor (UD) BM was used for 69 patients. GVHD prophylaxis consisted of single agent cyclosporine (CSP) for recipients of HLA-ID allografts and CSP, methotrexate, and methylprednisolone in recipients of UD BM. The median age of recipients was 45 years (range 21–70), with 55 males and 76 females. 43 pts were in CR1, 33 in CR2, and 55 had relapsed (rel) or refractory (ref) disease. 59 of 69 recipients of UD BM were serologically identical with their donors at 6/6 antigens. There were no graft failures in either group.With a median follow-up of over 18 months, the results of transplantation are presented in the Table.

Results of Transplantation

Clinical Outcome Allograft Source HLA-ID PB UD BM Grade 2–4 Acute GVHD 42% 51% Extensive Chronic GVHD 57% 61% Disease free survival (DFS) at 2 years CR1 49+/−10% 39+/−12% CR2 19%+/−12% 38+/−11% Rel/Ref 17+/−8% 0%

For pts transplanted in CR1, the results are comparable to those observed following fully ablative conditioning, particularly since many pts were transplanted due to high risk karyotype. In CR2, outcomes following RIC were superior in recipients of UD BM compared to HLA-ID PB, possibly due to a greater graft versus leukemia effect. UD BM was ineffective in pts with rel/ref AML. Of interest, the 2 year DFS in pts with rel/ref AML following receipt of HLA-ID PB was 17% overall, but was 28% in those that developed any acute GVHD versus 0% in those that did not (P<0.02). In conclusion, while the role of RIC in the treatment of pts with AML requires further clarification, our findings suggest that in pts beyond CR1, clinical evidence of donor alloreactivity appears to be critical for ensuring durable DFS.
Single Institution Experience with Two High-Dose Chemotherapy (HDC) Conditioning Regimens Prior to Autologous Stem Cell Transplant (ASCT) for Multiple Myeloma (MM).
Authors: Benson Don M. , Elder Patrick J. , Lin Thomas , Blum William , Penza Sam , Avalos Belinda , Byrd John C. , Copelan Edward , Farag Sherif S.
Published: April 2020

HDC with ASCT has become a standard treatment for patients with MM. Based on the results of recent trials, the use of melphalan (MEL) 200mg/m2 has emerged as the preferred HDC conditioning regimen, although research towards defining the optimal preparative regimen for these patients continues. We report our institution’s experience with two sequential patient cohorts receiving HDC regimens prior to ASCT as treatment for MM. From July 1992 through August 2003, 62 patients received the combination of high-dose busulfan (1 mg/kg orally every 6 hours for 14 doses on day −8 to −5), etoposide (60 mg/kg 36-hour continuous intravenous [IV] infusion on days −5 and −4) and cyclophosphamide (60 mg/kg/day IV on days −3 and −2) (BVC), and 48 patients received MEL 200 mg/m2 as a single IV dose on day −2). Prior to conditioning, peripheral blood stem cells were mobilized with etoposide or cyclophosphamide followed by filgrastim (gCSF) given subcutaneously at 10 μg/kg/day. At least 5 x 106 CD34+/kg ideal body weight was targeted for collection. Two patients in the BVC group had CD34+ cells harvested directly from bone marrow. In both groups, autologous stem cells were infused on day 0. Patients received aggressive supportive care measures including intravenous anti-emesis medications and analgesia as required, prophylactic antibiotics, blood product transfusion and filgrastim (gCSF) support. Patients treated with BVC and MEL were similar in age (median ages, 55 vs 58 years), MM subtype (IgG in BVC = 65%, IgG in MEL = 56%) and timing of transplant from diagnosis. Median time from diagnosis to transplant for BVC was 289 days (d), and for MEL was 287 d. 90% of BVC patients and 91% of MEL patients were receiving HDC/ASCT as second-line therapy. Whereas 39% of BVC patients and 58% of MEL patients had stage III disease, 30% of BVC patients and 23% of MEL patients were classified as having “progressive” or “refractory” disease at time of transplant. Median beta-2 microglobulin for BVC patients was 2.99 mg/dl and for MEL patients was 3.87 md/dl. Patients were similar in median length of hospitalization (BVC = 20 d vs MEL = 16 d), median duration of neutropenia (BVC = 9 d vs MEL = 10 d), and mdian duration of thrombocytopenia (BVC= 15 d vs MEL = 17 d). Toxicities of therapy were similar between groups, although there were two treatment related mortalities (TRM) in the BVC group (one attributed to infection, one to hepatic veno-occlusive disease). The median progression-free survival was similar between groups (BVC = 803 d vs MEL = 749 d, p > .05). The median overall survival (OS) for BVC pts was 1394 d while the median OS for MEL pts has not been reached to date (p>0.05). Our results indicate that MEL and BVC achieve similar long-term outcomes in patients with MM.
High Dose Therapy (HDCT) with Autologous Stem Cell Transplantation (ASCT) for Non-Hodgkin Lymphoma in the Elderly: Feasibility of a Patient-Tailored Treatment Plan.
Authors: Rupolo Maurizio , Michieli Mariagrazia , Spina Michele , Bernardi Daniele , Berretta Massimiliano , Giacalone Annalisa , Tirelli Umberto
Published: April 2020

HDCT followed by peripheral stem cell (PBSC) rescue is a suitable and effective option for patients (pts) affected by aggressive non-Hodgkin’s lymphoma (NHL) with chemosensitive disease at first relapse. Elderly pts are usually excluded from HDCT programs because of low stem cell collections and low tolerance to intensive chemotherapy. The Comprehensive Geriatric Scale (CGA) is a multidimensional pt evaluation that leads to the identification the therapeutic options. We designed a CGA-driven approach for elderly pts (between 60 and 75 years) affected by aggressive NHL in first relapse. Between October 23, 2000 and August 4, 2003 9 pts with NHL, 60 years of age and older were evaluated for ASCT at the Division of Medical Oncology A, National Cancer Institute, Aviano. Pts are stratified in 3 groups: 1) “frail pts” who do not undergo a HDCT program; 2) pts “at standard risk”, who scored 6 and 8 in the Activity of Daily Living (ADL) and Instrumental Activity of Daily Living (IADL) evaluation, respectively, with a Geriatric Depression Scale (GDS) score <11 and a Mini Mental Status (MMS) score >21 with a good respiratory function and no grade 2 comorbidities, who undergo a HDCT program with BEAM as conditioning regimen; 3) pts at “intermediate risk” who scored at least 5 and 7 in the ADL and IADL evaluation, respectively, with a GDS score <11 and a MMS score >21 and a score of no more than 2 in 1 to 3 comorbidities, who undergo a less aggressive HDCT program with double Melphalan 200 mg/m2 as conditioning regimen. Out of 9 pts 4 underwent to ASCT. The Data are summarized in table 1. CGA has emerged as a mandatory evaluation to guide therapeutic options and establish the prognosis of elderly patients. Stratification of patients into different prognostic groups according to a CGA can render HDCT a feasible and, possibly, effective procedure also in selected elderly patients affected by aggressive NHL.

Table

*Pt died after the first Melphalan transplant (interstitial pneumonia) M/F 6/3 Median age 66 (62–73; 75) Median PS 1 (0–2) # previous lines 1 (1–2) s-IPI 3 (1–4) Histology Large cell 7 Mantle 1 Follicular 1 Stage III 3 IV 6 HCV-positive 2 Salvage treatment ESHAP 3 R-DHAOX 6 Response pre-ABMT CR 6 PR 2 SD 0 PRO 1 CGA Frail 3 Standard risk 5 Intermediate risk 1 CD34+ harvest 4/9 CD34+ 10 6/kg 3.8 (2.3–4.6) ASCT Yes 3/5 standard risk No 3 frail, 1 intermediate risk* Status after transplant 1 CR +15 months 2 Relapses 6, 12 months
Phase I Study of Rituximab-Cyclophosphamide (R-CY) Stem Cell Mobilization and Rituximab-BEAM HDC with ASCT in Patients with Relapsed, Refractory or High Risk Intermediate Grade Non-Hodgkin’s Lymphoma.
Authors: Scigliano Eileen , Grosskreutz Celia L. , Fruchtman Steven M. , Gabrilove Janice L. , Mandeli John P. , Isola Luis M.
Published: April 2020

The addition of rituximab to mobilization regimens does not adversely affect collection of adequate numbers of CD34+ PBSC and may decrease tumor cell contamination. Prior administration of rituximab may sensitize lymphoma cells to chemotherapy, but its use with high dose chemotherapy has not been studied. In this study, eligible patients had intermediate grade NHL either primary refractory, relapsed or in CR1 with a high or intermediate/high risk IPI score. Five patients with a median age of 38 years (28–53) have been treated. All patients had rituximab previously. At transplant, 4 patients had relapse, chemosensitive to salvage in 3 patients, and untested in 1 patient. One patient had primary refractory disease, chemosensitive to salvage. Stem cell mobilization was rituximab 375mg/M2 followed by CY 2gm/M2/day for 2 doses and filgrastim 10ug/kg/d. Collection started when the CD34 count was ≥12/ul. High dose chemotherapy consisted of rituximab 375mg/M2 on day −8, carmustine 300mg/M2 on day −7, etoposide 200mg/M2/d on days −6 to −3, cytosine arabinoside 200mg/M2 on days −6 to −3 (8 doses) and melphalan 140mg/M2 on day −2. Patients received filgrastim post transplant and standard antibiotic prophylaxis. All patients are alive 11 to 306 days post transplant (median follow up 4.5 months). The median CD34+ cell dose collected was 8 x 106/kg (1.1 to 17.6). One patient had an inadequate CD34+ cell dose and required bone marrow harvesting which yielded 0.72 x 106/kg CD34+ cells. Engraftment of neutrophils and platelets occured at a median of 11 days post transplant. Infectious complications included febrile neutropenia in one patient following mobilization and in 4 patients following R-BEAM. Transient grade I–II (common toxicity criteria) hepatic enzyme elevation occurred in 2 patients following R-CY. Following R-BEAM, 3 patients developed grade II–IV LFT elevation without evidence of VOD, which resolved in two patients prior to discharge. The patient with grade IV hepatic toxicity had abnormal liver enzymes prior to study and known intrahepatic lymphoma. This patient continues to have grade III elevation of GGT 306 days post transplant with no evidence of infectious hepatitis or lymphoma (PET negative). One patient developed moderate hemorrhagic cystitis. One patient developed bilateral pulmonary infiltrates of unkown etiology (BAL negative for organisms) which resolved. R-CY was well tolerated as a mobilization regimen and led to adequate stem cell collection. R-BEAM HDC resulted in frequent elevations of LFTs. Further studies of rituximab with HDC warrant caution regarding hepatotoxicity.
High-Dose Sequential Chemotherapy (HDSC) in Support of Autologous Stem Cell Transplantation (ASCT) in Patients with Relapsed/Refractory Hodgkin Lymphoma (HL) and Non-Hodgkin Lymphoma (NHL).
Authors: Oyan Basak , Koc Yener , Ozdemir Evren , Kansu Emin
Published: April 2020

Background and aim: High-dose chemotherapy followed by ASCT is currently the standard treatment in achieving long-term survival in patients with relapsed or refractory HL and NHL. The aim of the present study is to assess the role of HDSC and ASCT in attaining high survival rates in patients with relapsed or refractory lymphoma.

Patients and Method: From 2000 to 2004, 42 patients with relapsed/refractory HL or NHL with a median age of 42 years (M:F=28:14) were treated with HDSC and ASCT. Only patients who were sensitive to salvage chemotherapy were eligible for the protocol, consisting of 3 phases. Phase I consisted of cyclophosphamide (4.5 g/m2) followed by G-CSF (10 mcg/kg/d) and PBSC collection. Phase II consisted of etoposide (2 g/m2) with G-CSF support of at 5 mcg/kg/d. The transplant phase consisted of mitoxantrone (60 mg/m2) and melphalan (180 mg/m2) followed by APBSC infusion.

Results: NHL patients had diffuse large cell (n=16), anaplastic large cell (n=4), mantle cell (n=2), follicular (n=2), small lymphocytic (n=2) and peripheral T cell (n=2) histology. Patients with HL had mixed cellular (n=7) and nodular sclerosing (n=7) histology. The rationale for ASCT was first relapse in 17 (41%) patients, more than one relapse in 14 (33%) patients, primary refractory disease in 10 (24%) patients and high risk disease in 1 (2%) patient. Prior to HDSC, 69% and 31% of the patients were in CR and PR, respectively. Patients received a median of 5.3x106/kg CD34+ cells. Median times to achieve neutrophil and platelet engraftments were 14 and 24 days, respectively. Transplant related mortality rate was 7% (n=3). At a median follow-up of 26 months (range, 1–48), 10 patients relapsed and 12 patients died. Causes of mortality were; veno-occlusive disease (n=1), infection (n=3), progression/relapse (n=6), congestive heart failure (n=1) and secondary AML (n=1). Five patients developed congestive heart failure (severe in one patient), mainly due to high cumulative doses of anthracyclines during the previous therapies. The estimated 3-year disease-free survival (DFS) and overall survival (OS) were 66.7% and 69.2% in HL patients and 75% and 77.4% in NHL patients, respectively. Regarding DFS and OS, there was no statistically significant difference between HD and NHL. Currently, 30 (71%) of patients are alive, of which 28 (67%) patients are in complete remission.

Conclusion: HDSC followed by APBSCT is an effective therapy in patients with relapsed/refractory NHL or HD, with an acceptable mortality rate.