scholarly journals How We Did Bone Marrow Transplants amidst the COVID19 Pandemic

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 40-40
Author(s):  
Kishore Kumar ◽  
Durai Prabhu ◽  
Dharani Devi ◽  
Dilshada Pulikkal ◽  
Joshua Daniel ◽  
...  
Keyword(s):  
Bone Marrow ◽  
British Journal ◽  
Cellular Therapy ◽  
Conflicts Of Interest ◽  
Single Point ◽  
Conditioning Regimen ◽  
Physical Interaction ◽  
Cell Transplant ◽  
Bone Marrow Transplants ◽  
Blood Banks

Introduction COVID19 is the most heard name for the last six months, and the situation seems to worsen now. This pandemic has created significant stress on the healthcare system. Most of the resources are being diverted to COVID care, and care of non-COVID patients is compromised. As haematologists dealing with frail immune-compromised patients, challenges we are facing are staff attrition, near-empty blood banks, less intensive care beds, the chance of our patients getting infected with COVID during the hospital stay, fear of donors being asymptomatic COVID carriers to mention a few. In this situation, we have tried to formulate a practical approach for doing bone marrow transplants, which we have been following for the last few months at our centre. Our Transplant Protocol Initially we tried to postpone transplants. But as the COVID situation was becoming a chronic one, we formulated our ways to start transplants. Amidst lockdown, we successfully completed Autografts in myeloma and Lymphoma. We also started Allogeneic transplants including haplo-identical transplant for acute leukemia. In this hour of need, we had to strike a balance in transplant management. We tried to be practical in our decision-making skills at this hour of need. Being students of science, it was time to show practicality in ordering tests, therapy, and transfusions to the patient. Due to lockdown and general panic, the stocks in Blood Banks were at an all-time low. So transfusions and donor arrangements were be dealt judiciously. The hospital was divided into COVID and NON-COVID zones. All patients with fever and respiratory symptoms go directly to the COVID zone and get examined and tested by physicians with proper PPE as per WHO protocol.Even there are no symptoms of COVID like dry cough, fever, and throat pain, the patients entering NON-COVID also will be screened by a general physician at the single point of entry with proper protection and then patient with one attendee was allowed to come to transplant outpatient department. This helped us reduce risk to the medical professional and other patients waiting in a specialty department like ours. We had a detailed discussion about the pros and cons with patient and attendee. We admitted them in a separate block and got tested for COVID19 RTPCR. The patient had HRCT thorax to check for early radiological signs of COVID19. The blood parameters which serve as prognostic markers for COVID were checked alongside to double confirm false negativity of tests.The donor was made to stay as attendee for the patient. We shifted them inside transplant unit and observed for a week to rule out COVID symptoms. Radiological investigations were done before starting procedure. Minimal physical interaction was established and in Myeloma and Lymphoma autograft, we did around 20% dose reduction of conditioning regimen drugs. For allograft, no drug dose modification was done. The threshold for antibiotic stewardship was kept very low and high end antibiotics like Colistin / Fosfomycin were initiated early. We collected single donor platelets and kept stocks ready to avoid exposure to multiple random donors. The blood bank also was very careful in selecting donors after a thorough screening for symptoms of COVID19. Once engrafted, they were discharged early and kept on follow-up mostly by tele-consultation. The personal visits were kept to a minimum of once in four weeks. From first lockdown to date of submission, we completed nine bone marrow transplants at our centre which included three AML haplo-identical transplants. Conclusion Postponing transplant is not feasible in all situations, as few of our refractory diseases will ultimately relapse and transplant becomes the only live saving procedure. As we wait for the situation to better, the normal functioning of hospitals may take some more time.These above are the methods we are following in our MIOT hospital at Chennai, India the city which has got around 100,000 COVID19 cases during submission. Our advice is where ever feasible, we should try to stick to time tested conventional protocols. The above protocols may be useful temporarily till the COVID crisis is over. Reference Willian J. Care of hematology patients in a COVID-19 epidemic. British Journal of Hematology, 2020.Dholaria, Savani B.N. How do we plan hematopoietic cell transplant and cellular therapy with the looming COVID-19 threat? British Journal of Haematology, 2020.https://doi.org/10.1111/bjh.16597 Disclosures No relevant conflicts of interest to declare.

KIT Blockade Is Sufficient to Sustain Donor Hematopoietic Stem Cell Engraftment in Fanconi Anemia Mice

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1206-1206
Author(s):  
Shanmuganathan Chandrakasan ◽  
Rajeswari Jayavaradhan ◽  
Ernst John ◽  
Archana Shrestha ◽  
Phillip Dexheimer ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Fanconi Anemia ◽  
Conflicts Of Interest ◽  
Bone Marrow Failure ◽  
Conditioning Regimen ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Increased Risk

Abstract Background: Fanconi anemia (FA) is the most common cause of inherited bone marrow failure (BMF). Currently, the only curative option for the BMF in FA is an allogenic hematopoietic stem cell transplant (HSCT). However, due to the underlying DNA repair defect, FA patients poorly tolerate alkylating chemotherapy or irradiation based conditioning, which is necessary for donor engraftment. However, this results in significant short and long term morbidity/mortality and augments the inherent increased risk of malignancies in FA patients. To overcome the adverse effects associated with alkylating conditioning agents, alternate experimental approaches exploiting the inherent hematopoietic stem cell (HSC) defect in FA are of utmost clinical necessity. Objective: To develop a safe KIT blocking antibody (KIT-Ab) based HSCT conditioning regimen for FA that does not involve chemotherapy or irradiation. Method: High purity KIT-Ab was made from the ACK2 hybridoma and its specificity to KIT binding was validated using mast cell assay. Baseline peripheral blood cells and the bone marrow hematopoietic stem and progenitor cell (HSPC) compartment (Lin-Kit+Sca+ and Lin-Kit+Sca+CD150+CD48- cells) of FANCA-/- and FANCD2-/- murine models were analyzed. Mechanistic studies using sorted FA bone marrow HSPC were performed ex vivo. This was followed by definitive primary and secondary transplants experiments following injection of KIT-Ab. Results: Several features of FA hematopoietic stem/progenitor cells (HSPC) suggested their susceptibility to KIT-Ab blockade-mediated killing: (a) Expression of KIT was significantly lower in FANCA-/- HSPC, while expression of its ligand was higher in bone marrow stroma; (b) Moreover, genes associated with apoptosis/senescence, stress and inflammatory signaling that were upregulated in WT-HSPC following KIT-Ab blockade, were upregulated in FANCA-/- HSPC at baseline; (c) Furthermore, FANCA-/- HSPC demonstrated increased susceptibility to KIT-Ab mediated apoptosis and had a reduced proliferative capacity. In-vivo studies following ACK2 injection showed a marked reduction of colony-forming units (CFU-C) from both FANCA-/- and FANCD2-/- mice one week following injection, when compared to WT mice (48% and 76% decrease in CFU-C, respectively). Based on these findings, we evaluated the role of ACK2 as a sole HSCT conditioning regimen in FANCA-/- and FANCD2-/- mice. Indeed, definitive HSCT in both FANCA-/- and FANCD2-/- mice using KIT-Ab based conditioning resulted in donor HSC engraftment with multi-lineage chimerism, which progressively increased to 22-24% by 4-months, and was sustained in secondary transplants. Overall, we show that KIT-blockade alone is an adequate non-genotoxic HSPC-targeted conditioning in FA mice, and its clinical translation could circumvent the extensive transplant-related morbidity/mortality in this disease. Disclosures No relevant conflicts of interest to declare.

scholarly journals The Platelet Millionaire: A Rare Cause of Thrombocytosis in an Adolescent

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5391-5391
Author(s):  
Ritika Walia ◽  
Theresa Sepulveda ◽  
Sharon Wretzel ◽  
Philip H Brandt
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Biopsy ◽  
Primary Care Physicians ◽  
Conflicts Of Interest ◽  
Abdominal Ultrasound ◽  
Cell Transplant ◽  
Peripheral Smear ◽  
Hematopoietic Stem ◽  
Marrow Fibrosis

Objectives: Primary myelofibrosis is rare in pediatrics, often manifesting as persistent idiopathic thrombocytosis.Transitions from pediatric to adult medical care can be complicated by workup requiring invasive procedures. J.M., an 18-year-old healthy male, presented for excessive gingival bleeding after wisdom tooth extraction. Workup revealed persistent thrombocytosis to 1,165K, prompting a referral to hematology-oncology. A peripheral smear was notable for many platelets but normal RBC morphology. He had splenomegaly on abdominal ultrasound and a decreased von-Willebrand's activity to antigen ratio, suggesting acquired vWD. A bone marrow biopsy was advised; however, J.M. became lost to follow up for over 9 months owing to self-reported anxiety about the procedure. He remained asymptomatic in this interim until he re-presented to clinic for easy bruising, with no other evidence of bleeding at the time. The biopsy was pursued, revealing hypercellular marrow for age with left shifted granulocytic and erythroid maturation, abnormal megakaryocytes, and 3% blasts. This was consistent with primary early myelofibrosis (PMF), positive for MF-1, CALR, and TP53 mutations and negative for JAK2 and BCR-ABL. He was transitioned to adult hematology, maintained on baby aspirin, and referred for potential allogeneic hematopoietic stem cell transplant (HSCT). PMF is characterized by marrow fibrosis due to secretion of fibroblast growth factor by clonally proliferative megakaryocytes. It is a disease of adulthood, with 67 years being the median age at diagnosis. Only 100 cases have been reported in children, most of which are secondary to AML, ALL or other malignancies.1 Most patients present with complications of extramedullary hematopoiesis or bleeding.2 Diagnosis is suggested by a leukoerythroblastic picture on peripheral smear and confirmed with a bone marrow biopsy "dry tap" revealing marrow fibrosis.3 Prognosis in pediatric PMF is difficult to predict but outcomes tend to be worse;4 TP53 mutation is rare and based on limited adult studies may portend a poorer prognosis.5 Our young patient with this rare mutation was therefore referred for HSCT evaluation. Further complicating this case was J.M.'s anxiety, which delayed definitive diagnosis by biopsy. He only agreed to it when, at the med-peds clinic, the concept of local pain management was discussed. Anticipation of upcoming procedures by primary care physicians and close follow-up is especially important for patients transitioning from pediatric to adult providers. Disclosures No relevant conflicts of interest to declare.

Anti-Third Party Veto Cells Facilitate Allogeneic Hematopoietic Cell Engraftment in MHC-Mismatched Dogs.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2138-2138
Author(s):  
Marina Lesnikova ◽  
Alla Nikitine ◽  
Rainer F. Storb ◽  
Richard A. Nash ◽  
George E. Georges
Keyword(s):  
Bone Marrow ◽  
Nk Cells ◽  
Graft Rejection ◽  
Fas Ligand ◽  
Conditioning Regimen ◽  
Hematopoietic Cell ◽  
Host Cells ◽  
Unrelated Donor ◽  
Cell Transplant ◽  
Veto Cells

Abstract Donor-derived veto cells have the potential to facilitate engraftment of major histocompatibility complex (MHC)-mismatched marrow by neutralizing radioresistant host T and NK cells that mediate rejection of the donor graft. Anti-3rd party cytotoxic T-lymphocyte (CTL) veto activity is CD8 and Fas ligand dependent (Reich-Zeliger et al., Immunity, 2000) and studies in murine models of hematopoietic cell transplantation (HCT) showed that CTL veto cells facilitate engraftment across MHC barriers (Bachar-Lustig et al., Blood, 2003). To translate these results to the well-established pre-clinical dog model of HCT, we had previously demonstrated that donor-derived, anti-3rd party CTL that are not alloreactive against host cells could function as veto cells and block the emergence of host-derived, anti-donor CTL in vitro. Previous studies showed that DLA-nonidentical, unrelated bone marrow grafts were uniformly rejected by host T and NK cells following 920 cGy total body irradiation (TBI) without postgrafting immunosuppression (90% of dogs with graft rejection). In the current study we asked if infusion of donor derived, anti-3rd party CTL veto cells could facilitate engraftment of MHC-mismatched marrow. To date, six recipient dogs have been transplanted. For each hematopoietic cell transplant, four DLA-nonidentical, unrelated dogs were used: one marrow donor, one marrow recipient and two 3rd party dogs. Dendritic cells (DC) were cultured from bone marrow CD34+ cells obtained from 3rd party dogs. Ten days before transplant, donor lymphocytes were collected by leukapheresis and cultured separately with 3rd party DCs to generate anti-3rd party CTL veto cells. On day 0, recipients were irradiated with 920 cGy TBI and transplanted with donor bone marrow (2.3–5.4x108 TNC/kg; 4–12x106 CD34+/kg) and donor derived anti-3rd party CTL veto cells (30–57 x106 cells/kg). Three of six (50%) dogs engrafted 7 to 18 days after HCT (as determined by bone marrow biopsy, complete donor hematopoietic chimerism and recovery of absolute neutrophil count >500/μL) and developed 3-system graft-versus-host disease (GVHD). The other 3 dogs had transient donor engraftment with clinical and histopathological evidence of GVHD. Dogs were euthanized between days 14 and 19 after HCT. In contrast, none of five historical control dogs engrafted after transplantation with DLA-nonidentical, unrelated donor marrow and 30-40x106/kg freshly isolated donor peripheral blood mononuclear cells, p<0.05 (Panse JP et al., Transplantation, 2003). These preliminary data suggest that donor derived, anti-3rd party CTL veto cells eliminate host-anti-donor T and NK cell responses and facilitate engraftment of MHC-mismatched marrow. Future studies will aim to transplant veto cells with T-cell-depleted marrow and administer post-grafting immunosuppression to decrease the intensity of the conditioning regimen needed for MHC-mismatched HCT engraftment without risking graft rejection or GVHD.

5-Azacytidine Before or After Stem Cell Transplantation in Acute Myeloid Leukaemia (AML) and Myelodysplastic Syndromes (MDS)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4267-4267
Author(s):  
Ana Garrido ◽  
Miguel Ortín ◽  
Rodrigo Martino ◽  
Josep Nomdedeu ◽  
Ana Aventin ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Disease Progression ◽  
Cell Transplantation ◽  
Conflicts Of Interest ◽  
Conditioning Regimen ◽  
Complete Response ◽  
Cell Transplant ◽  
Safe Procedure

Abstract Abstract 4267 The acceptable toxic profile of 5-aza-citidine (5-aza) allows its use in fragile or elderly patients in whom intensive chemotherapy should be avoided. Whether it is possible to take advantage of this low toxicity in patients awaiting for donor search and/or stem cell transplant (SCT) and in those experiencing leukemia recurrences after the procedure remains unknown. We analysed the clinical results of using 5-aza in these two settings to define the feasibility, safety and results of this approach. Patients and methods: From 2007 to 2011, 15 patients (11 males, 4 females) received 5-aza as last treatment prior to an allogeneic SCT (n=13) or as rescue after an early post-transplant relapse (n=2) at our centre. Diagnosis was MDS in 3 cases (median age 62; range 58–63) and AML in 12 cases (median age 58; range 37–67). Patients with MDS received a median of 6 courses of 5-aza (range 3–8) as the only treatment from diagnosis, except for one patient who had received panobinostat prior to 5-aza. Amongst patients with AML, 12 patients received 5-aza either as treatment for AML (2/12) or after remission (8/12) because of the high relapse risk while awaiting for a suitable donor to be found. Two patients with AML received 5-aza as treatment for early post-SCT relapse. AML patients treated with 5-aza before SCT received a median of 5 courses (range 1–19), whilst patients receiving treatment for relapse received 1 and 3 courses, respectively. Ten patients received a nonmyeloablative conditioning regimen, 1 received a conventional conditioning regimen, 2 patients are still in the process of donor search and the other 2 patients received 5-aza after an autologous stem cell transplantation relapse. RESULTS: All MDS patients engrafted and are in complete remission (CR) after a median of 696 days of follow-up (range 377–1227). One of those patients died because of aGvHD. Nine of 12 AML patients receiving 5-aza prior to SCT are alive after a median 373 days follow-up (133–995). One patient showing refractoriness to 3 different lines of treatment died from disease progression after 211 days. All patients receiving 5-aza as treatment for early relapse are dead, 41 and 401 days after starting treatment. Most interestingly, AML patients receiving 5-aza as maintenance of an already-achieved CR while awaiting transplantation did not experience disease progression despite the median time they remained on this treatment was prolonged (9 months). Graft-versus-host disease ≥ grade II was seen in 3 patients. No graft failures were seen and all patients who received an allogeneic stem cell transplantation remain in complete response. CONCLUSION: The use of 5-aza for maintaining or achieving a response in patients with AML who are awaiting SCT is a safe procedure and adds flexibility to schedule the treatment without the need to administer potentially toxic therapy. The use of 5-aza before transplant did not appear to interfere either with engraftment, incidence of GvHD or short-term relapse after transplant. Disclosures: No relevant conflicts of interest to declare.

Anti-CD45 Radioimmunotherapy Using the Alpha-Emitting Radionuclide 211At Combined with Bone Marrow Transplantation Prolongs Survival in a Disseminated Murine Leukemia Model

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4096-4096
Author(s):  
Johnnie J. Orozco ◽  
Aimee Kenoyer ◽  
Tom Bäck ◽  
Ethan R. Balkin ◽  
Donald K. Hamlin ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Renal Function ◽  
Path Length ◽  
Conflicts Of Interest ◽  
Energy Levels ◽  
Radiation Doses ◽  
Cell Transplant ◽  
Normal Ranges ◽  
Dose Dependent ◽  
Murine Leukemia

Abstract Abstract 4096 Background: Despite aggressive hematopoietic cell transplant (HCT) strategies, many patients with acute myeloid leukemia (AML) relapse. Our group has explored radioimmunotherapy (RIT) using anti-CD45 antibodies (Ab) labeled with β-emitting radionuclides such as 131I and 90Y as a means to augment cytotoxicity and reduce relapse. This approach has been limited by their low energy levels (0.66–2.3 MeV) and potential non-specific toxicities due to their relatively long path lengths (0.3–2.3 mm). Conversely, α-emitting agents display higher energy levels (8 MeV) delivered over a short path-length (∼60–80 μm) that can lead to superior therapeutic ratios of absorbed radiation doses that may reduce AML relapse. For this purpose 211At is an α-emitter with an attractive half-life (7.2 hours), energy profile (6.8 MeV averages of two alpha decays, 5.9 and 7.5 MeV) and path length (average range 55–70 μm). Therefore, we evaluated the efficacy and toxicity of anti-CD45 RIT using 211At in a clinically relevant CD45+disseminated murine leukemia model. Methods: SJL/J mice were given 105 syngeneic SJL leukemic peripheral blood mononuclear cells (PBMCs) via tail vein, followed two days later by211At-labeled anti-murine CD45 Ab-decaborate(2-) conjugate (30F11-B10) or 211At-labeled negative control Ab-decaborate(2-) conjugate (rat IgG-B10) in tissue biodistribution studies. Groups of 5 mice were euthanized 6, 24 and 48 hours later and organs were harvested and analyzed in a gamma counter to yield percent of the injected dose per gram (% ID/g). To assess toxicities associated with this approach, SJL/J mice were treated with 12–24 μCi of 211At-30F11-B10 and then evaluated weekly thereafter for impact on blood counts, as well as changes in hepatic and renal function. In HCT therapeutic studies, groups of 10 leukemic mice per dose were injected with 12–24 μCi of 211At-30F11-B10 or 211At-rat Ab-B10, followed two days later by rescue with 15 × 106 syngeneic bone marrow (BM) cells. Results: Delivery of 211At-30F1-B10 demonstrated excellent localization to the BM and spleen at 24 hours (79 and 18% ID/g, respectively) post injection with lower kidney and lung uptake (8.4 and 8.3% ID/g, respectively) at the same time point. Anti-CD45 RIT using 211At-30F11-B10 followed by syngeneic HCT led to a dose-dependent survival benefit in leukemic mice with a median survival (OS) of 120, 98 days, and 62 days for animals treated with 24, 20, and 12 μCi 211At-30F11-B10, respectively, compared with untreated control mice (median OS of 36 days) and mice treated with non-specific 211At-labeled rat Ab-B10 (median OS of 46 days) (Figure). Moreover, anti-CD45 RIT with 211At-30F11-B10 led to minimal toxicity with mild dose dependent leukopenia as the most pronounced lab abnormality. White blood cell count nadir was between 2.5 and 4.2 k/μL two weeks after HCT for mice treated with 24 and 12 μCi 211At-30F11-B10, respectively. Counts recovered to normal levels (6–8 K/μL) 4 weeks after HCT. Mild increases in transaminase levels were seen in mice that received 211At-30F11-B10, yet these values remained within the normal ranges (ALT 68–75 IU/L; AST 155–170 IU/L). Renal function after 211At-30F11-B10 did not significantly deviate from baseline (BUN 15–17 mg/dL; Cr 0.3–0.4 mg/dL). Conclusion: Taken together, these data suggest that anti-CD45 RIT using the α-emitting radionuclide 211At in conjunction with HCT is a promising therapeutic option for AML. Excellent targeting of radiation doses to BM and spleen was demonstrated with a favorable toxicity profile. Further investigation of anti-CD45 RIT for AML using 211At in clinical trials appears to be warranted. Disclosures: No relevant conflicts of interest to declare.

Gemtuzumab Ozogamicin (GO) in Infants with Acute Myeloid Leukemia (AML) – Combined Results from the Children’s Oncology Group (COG) Trials, AAML03P1 and AAML0531

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 377-377
Author(s):  
Erin M. Guest ◽  
Richard Aplenc ◽  
Lillian Sung ◽  
Susana C. Raimondi ◽  
Betsy A. Hirsch ◽  
...  
Keyword(s):  
Bone Marrow ◽  
High Risk ◽  
De Novo ◽  
Conflicts Of Interest ◽  
Bone Marrow Failure ◽  
Early Death ◽  
Gemtuzumab Ozogamicin ◽  
Juvenile Myelomonocytic Leukemia ◽  
Cell Transplant ◽  
Intensive Chemotherapy

Abstract Background: Infants <1 year of age with AML are at high risk of early death during induction, pulmonary and infectious toxicities, and treatment related mortality (TRM). Compared with older children, infants are more likely to have higher risk clinical and cytogenetic features. Targeted therapy is needed to improve the outcomes for infants with AML while minimizing toxicities. Objective: To determine if the addition of gemtuzumab ozogamicin (GO) to standard chemotherapy is safe, tolerable, and improves event free survival (EFS) in infants <1 year of age with AML. Methods: Infants >/= 1 month to <1 year of age with de novo AML or <1 month of age with progressive AML were eligible for enrollment on the COG trials AAML03P1 and AAML0531. Infants with acute promyelocytic leukemia, juvenile myelomonocytic leukemia, bone marrow failure syndromes, or Down syndrome were not eligible. The 5-course chemotherapy backbone was identical in both trials. GO 3 mg/m2/dose (0.1 mg/kg for patients with a body surface area <0.6 m2) was given on day 6 of Induction (Ind) I and day 7 of Intensification (Int) II to all patients on AAML03P1 and to randomized patients on the experimental arm of AAML0531. Patients on the control arm of AAML0531 were treated with standard therapy without GO (noGO). Stem cell transplant (SCT) was given following IntI to patients on AAML03P1 with a matched family donor (MFD) and to patients on AAML0531 with high risk (HR) disease or with intermediate risk (IR) disease and a MFD. SCT recipients only received one dose of GO. Patients were removed from protocol if the bone marrow had >/= 20% blasts after IndI on AAML03P1 or >/= 5% blasts after IndII on both studies. Early death (ED) was defined as death during IndI. Results: AAML03P1 enrolled 39 infants from 2003-2005 and AAML0531 enrolled 103 infants from 2006-2010 (Table 1). Median follow up was 5.02 years. The demographics and disease characteristics of infants enrolled on both studies were similar. Compared with enrolled children >/= 1 year of age, infants had higher frequencies of hepatomegaly (p<0.001), splenomegaly (p<0.001), hyperleukocytosis (WBC>100x103/µL, p=0.003) and French-American-British (FAB) M5 (p<0.001), and M7 (p<0.001) AML. Infants had less FAB M1 (p<0.001), M2 (p<0.001), and M4 (p=0.029) AML. There was no difference in CNS disease by age. The frequency of 11q23/MLL rearrangement was highest in infants 0-179 days of age (44%) and significantly decreased with increasing age (p<0.001). Favorable cytogenetics were rare in infants: t(8;21) was not found and inv(16)/t(16;16) was only found in 4 patients. FLT3-ITD HAR was absent in infants. The majority of infants (89%) fell into the IR group and infants were less likely to have had high (HR) or low risk (LR) disease when compared with children >/= 1 year. Table 1: Combined characteristics of infants on AAML03P1 and AAML0531 Table 1:. Combined characteristics of infants on AAML03P1 and AAML0531 The ED rate was higher in younger infants (7 ED, infants 0-179d) when compared with older infants (1 ED, infants 180-364d) (p=0.013). EDs were not increased in infants who received GO vs. noGO (5 vs. 3 ED, p=0.730). The complete remission (CR) rate for infants was 68% at the end of IndII. The 5 year EFS was lower in infants than children >/= 1 year (42 vs. 50%, p=0.001). The 5 year OS for infants was 62%, relapse risk (RR) was 44%, and TRM was 10%. Infants who received GO had improved OS, EFS, and RR, though the differences were not statistically significant (Table 2). Table 2: Combined outcomes of infants on AAML03P1 and AAML0531: noGO vs. GO Conclusion: GO in combination with intensive chemotherapy is tolerable in infants with AML, does not increase early deaths, and is associated with trends toward improved EFS, OS, and RR. Table 2:. Combined outcomes of infants on AAML03P1 and AAML0531: noGO vs. GO Conclusion: GO in combination with intensive chemotherapy is tolerable in infants with AML, does not increase early deaths, and is associated with trends toward improved EFS, OS, and RR. Disclosures No relevant conflicts of interest to declare.

Impact of Infusion Rate on the Early Engraftment Following Allogeneic Intra Bone Marrow Infusion of Hematopoietic Stem Cells in a Canine DLA-Identical Reduced Intensity Transplantation Model

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5406-5406
Author(s):  
Stephanie Schaefer ◽  
Juliane Werner ◽  
Sandra Lange ◽  
Katja Neumann ◽  
Christoph Machka ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Hematopoietic Stem Cells ◽  
Infusion Rate ◽  
Conflicts Of Interest ◽  
Conditioning Regimen ◽  
Hematopoietic Stem ◽  
Time Points ◽  
The Impact ◽  
Reduced Intensity

Abstract Introduction: Direct intra bonemarrow (IBM) infusion of hematopoietic stem cells (HSC) is assumed to improve the homing efficiency and to accelerate the early engraftment in comparison to the conventional intravenous application of HSC. Especially for transplantation of low cell numbers i.e. "weak grafts" that is generally associated with delayed engraftment. The direct infusion of HSC in close proximity to the HSC niche by intra bone marrow transplantation (IBMT) might be a promising way. Whether the HSC infusion rate might influence the homing process and therefore the outcome after IBMT is so far unknown. Aims: Herein, we analyzed in a canine DLA-identical littermate model the impact of different graft infusion rates on the hematopoietic recovery as well as on the engraftment kinetics after IBMT following reduced intensity conditioning. Methods: Recipient dogs received IBMT following a 4.5 Gy total body irradiation (TBI). From day (d) -1 until d+35 Cyclosporin A (15mg/kg) was administered orally twice a day as immunosuppression. For IBM transfusion the graft volume was reduced by buffy coat centrifugation and dogs obtained 2x25 ml simultaneously into the humerus and femur. The infusion rate of the graft was 25ml/10 min in group 1 (IBM10, n = 8) and 25 ml/60 min in group 2 (IBM60, n = 7). A 28 day follow-up is currently available for twelve dogs (IBM10 n = 7; IBM60 n = 5). The development of the peripheral blood mononuclear cell (PBMC) and granulocyte chimerism was tested weekly. Blood count, kidney and liver enzymes were monitored routinely. Results: All animals engrafted. One dog of the IBM10 group died at d+15 (infection) and was therefore not included into analysis. The median number of infused total nucleated cells were in IBM10 4.1*108/kg (range 2.3-6.0*108/kg) and in IBM60 3.2*108/kg (range 1.8-4.4*108/kg; p=0.4). The infused CD34+ numbers were median 3.2*106/kg (range: 1.2-10.0*106/kg; IBM10) and 3.6*106/kg (range: 1.5-6.8*106/kg; IBM60; p=0.7). Time of leukocyte recovery was median d+11 after IBMT in both groups (range: d+4 to d+11, IBM10; d+8 to d+14, IBM60; p= 0.5). Median leukocytes nadirs amounted to 0.2*109/l for IBM10 and 0.3*109/l for IBM60 (p= 0.08). The median duration of leukopenia (<1*109/l) were similar (6d, range: 4-11d, IBM10; 3-9d, IBM60) (p= 0.6). Median platelet nadir was 0*109/l for both cohorts (range: 0.0-7.0*109/l, IBM10; 0.0-1.0*109/l, IBM60). The period of thrombocytopenia (≤20.0*109/l) was significantly prolonged in the IBM60 group (median 10d, range) compared to 5d (range: 3-12d) in the IBM10 group (p=0.05). Donor PBMC chimerisms at d+7, d+14 and d+28 were median 22% (range: 8-34%), 50% (range: 29-53%) and 67% (range: 47-73%) in IBM10. The results of PBMC chimerism for IBM60 were 11% (range: 5-34%), 42% (range: 20-42%) and 59% (range: 44-66%) at these time points (p = n.s.). Donor granulocyte chimerisms of median 33% (range: 11-83%), 100% (range: 58-100%) and 100% (range: 82-100%) were detected at d+7, d+14 and d+28 after HSCT in IBM10, respectively. The granulocyte chimerism in IBM60 amounted to 34% (range: 3-87%), 96% (range: 94-100%) and 98% (range: 96-100%) at the above mentioned time points p=n.s. for all time points). Conclusion: Our data suggest that early granulocyte and PBMC engraftment is not influenced by modification of the HSC infusion rate. However, the period of thrombocytopenia seems to be prolonged following a 60 minutes application. Therefore, longer infusion times in an IBMT setting seem not to be beneficial following toxicity reduced conditioning regimen. Disclosures No relevant conflicts of interest to declare.

Impact of Cytopenia Following Unmanipulated Haploidentical Hematopoietic Stem Cell Transplantation Using Post-Transplant Cyclophoshamide

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2281-2281
Author(s):  
Villetard Ferdinand ◽  
Stefania Bramanti ◽  
Samia Harbi ◽  
Sabine Fürst ◽  
Catherine Faucher ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cell Transplantation ◽  
Disease Risk ◽  
Conflicts Of Interest ◽  
Risk Index ◽  
Conditioning Regimen ◽  
Post Transplantation ◽  
Hematopoietic Stem ◽  
Cell Dose ◽  
The Impact

Abstract Introduction Allogeneic transplantation from a haploidentical donor (HaploSCT) is an alternative strategy in the treatment of hematologic malignancies in absence of HLA-identical donor. Recent studies reported similar outcome after HaploSCT compared to HLA-identical transplantation in different settings (Bashey, JCO 2013; Wang, Blood 2015; Gosh, JCO 2016). Although survivals seemed promising after HaploSCT, hematopoietic recovery following such a mismatched transplantation could represent a limitation. Thus, our series aims to evaluate hematological recovery after HaploSCT using a post transplantation cyclophosphamide (PT-Cy) platform. Methods This retrospective monocentric study included consecutive patients with following criteria: adults with hematological malignancies; bone marrow or peripheral blood T-replete HaploSCT from 2011 to 2015; non-myeloablative (Baltimore approach) or reduced intensity conditioning (busulfan-based) regimen; PT-Cy as part of GVHD prophylaxis. Patients with primary graft failure were excluded. Absolute neutrophil count (ANC), red cells (RCT) or platelet transfusion (PT) requirements on day 30 (D30) and day 100 (D100) were analyzed among disease-free patients. We first separately evaluated the rate of patients with significant cytopenia in each lineage (defined by ANC < 1 G/L, RCT need, PT need) and searched for impact of pre-transplantation factors on cytopenia (multivariate analyses by binary logistic regression). Then, we evaluated outcome by D30- and D100-landmark analyses according to cytopenia. Results One hundred and forty six patients with a median age of 56 years (range: 19-73) were analyzed: 142 and 117 were evaluable at D30 (4 early deaths) and D100 (17 deaths, 11 relapses), respectively. At D30, 20% of patients had ANC<1G/L, 67% needed RCT and 63% needed PT. Corresponding values at D100 were 20%, 42% and 28%, respectively (Figure 1). At D30: the use of PBSC (HR 9.5, p=0.002) was significantly associated with ANC>1G/L at D30; the use of NMAC Baltimore schema (HR 0.3, p=0.012) and CD34+ cell dose > median (HR 0.4, p=0.041) decreased PT needs while hematopoietic cell transplantation comorbidity index (HCT-CI)≥3 (HR 3.3, p=0.004) was associated with PT needs; no factor was found to significantly influence RCT. At D100: Age>60 years (HR 2.4, p=0.045), female to male HaploSCT (HR 3.3, p=0.020) and HCT-CI≥3 (HR 3.7, p=0.006) were significantly associated with higher risk of RCT need; female to male HaploSCT (HR 3.6, p=0.015) and HCT-CI≥3 (HR 6.9, p=0.001) were associated with PT needs; no factor was found to significantly influence ANC. With a median follow up of 25 months (range: 5-55), cox multivariate model with adjustment by age (continuous), disease risk index (low/intermediate vs high/very high), HCT-CI (0-2 vs ≥3), conditioning regimen (baltimore vs. busulfan-based) and graft source (bone marrow vs PBSC) showed that ANC<1 G/L was strongly associated with higher NRM (HR 2.9, p=0.011) and shorter OS (HR 3.4, p<0.001), overcoming the impact of RCT and PT needs (Figure 2A and 2B). In contrast, D100 analysis showed that PT need was the most determinant factor of increased NRM (HR 13.7, p=0.013) and poor OS (HR 7.3, p=0.003), while both D100 ANC and RCT needs did not impact outcome (Figure 2C and 2D). Discussion We found that cytopenia remain a concern after HaploSCT, leading to increased NRM and OS. The absence of ANC>1G/L at D30 as well as the need of PT at D100 may be considered as a strong post transplantation factor predicting poor outcome. Some pre-transplantation factors of cytopenia have been identified, such as CD34+ cell dose, sex mismatch and graft source. Among them, some may help for donor selection while the optimal donor for HaploSCT is still unknown. Moreover, better neutrophil recovery at D30 is achieved with the use of PBSC. CD34+ optimal cell dose in this setting remains also to be determined. In addition, post transplantation events such GVHD and/or infections should be evaluate to explore their interactions with such cytopenia, aiming to develop early therapeutic interventions. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

Excelent Option Therapy of BONE Marrow Failure in Fanconi Anemia Patients Withouth Full Match Donnor

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5075-5075 ◽  
Author(s):  
Lisandro L Ribeiro ◽  
Samantha Nichele ◽  
marco Antonio Bitencourt ◽  
Ricardo Petterle ◽  
Gisele Loth ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Conflicts Of Interest ◽  
Bone Marrow Failure ◽  
Hematological Parameters ◽  
Severe Neutropenia ◽  
Cell Transplant ◽  
Variable Degree ◽  
Duration Of Treatment ◽  
Hematopoietic Stem ◽  
Hematological Response

Abstract The main cause of morbidity and mortality of FA pts is bone marrow failure (BMF), which usually arises in the first decade of life and progresses to transfusion dependence and severe neutropenia. Androgen treatment has been recommended for FA pts with BMF for whom there is no acceptable hematopoietic stem cell transplant donor. Oxymetholone and Danazol are frequently used in these pts. We retrospectively analyzed data on 67 FA pts who received oxymetholone or danazol for the treatment of their BMF. The starting dose was approximately 1mg/kg for oxy and 2-4mg/kg for danazol. The hematological parameters at the initiation of treatment were hemoglobin (Hb) < 8 g/dL and/or thrombocytes < 30.000/μl. Patients were diagnosed between 01.2005 and 01.2016. The median age was 10.5 ys (2.9 - 40ys). Gender: 39M/27F. The median duration of treatment was 18m (3m - 95m). Fifty-three patients (79%) showed hematological response and became transfusion independence at a median of 3 months after beginning oxymetholone (2-9m) and 5 months after danazol (4-7m). Two adult pts treated with danazol achieved total hematological response with 2.5mg/kg. Seven pts are stable after tapering and stopping androgen with a median follow up of 4 ys (6m-8.5ys). Fourteen pts did not respond to treatment (21%). Eleven pts received an HSCT and seven are alive and well. Three pts were not transplanted and two are alive but transfusion dependent and one pt died from CNS bleeding. All patients developed variable degree of virilization but it was more evident with oxymetholone therapy. Older age at starting therapy was related to less virilization. Conclusion: This study shows the largest number of FA pts treated with androgen up till now. Androgen is an effective and well-tolerated treatment option for FA pts who develop BMF with 79% of them showing transfusion free after 3-5 months. This response may give us time to search for better donors. Disclosures No relevant conflicts of interest to declare.

scholarly journals Minimal Residual Disease (MRD) By Either Flow Cytometry or Cytogenetics Prior to an Allogeneic Hematopoietic Cell Transplant (allo-HCT) Predicts Poor Acute Myeloid Leukemia (AML) Outcomes

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3221-3221
Author(s):  
Lakshmikanth Katragadda ◽  
Maxim Norkin ◽  
Myron Chang ◽  
Yunfeng Dai ◽  
Jan S Moreb ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Complete Remission ◽  
Conflicts Of Interest ◽  
Univariate Analysis ◽  
Conditioning Regimen ◽  
Cox Proportional Hazards Model ◽  
Cell Transplant ◽  
Poor Risk ◽  
The Impact ◽  
Count Recovery

Abstract Introduction: Persistent AML is a known risk factor for poor outcomes after allo-HCT. The impact of MRD in patients who achieve complete remission (CR) or CR with incomplete count recovery (CRi) has been less well studied. Methods: We retrospectively reviewed the records of AML patients who underwent allo-HCT in morphological remission (<5% myeloblasts and normal marrow cellularity) with or without blood count recovery between January, 2000 and January, 2014. Data was collected for variables known to impact the prognosis of AML patients (Table 1). MRD was defined as evidence of abnormalities associated with AML by either flow cytometry, cytogenetics or Fluorescence in situ hybridization (FISH). The impact of MRD identified at the time of allo-HCT on cumulative incidence of relapse (CIR), progression free survival (PFS), and overall survival (OS) was assessed in MRD+ and MRD- patients. Results: A total of 166 eligible patients were identified. The median follow-up among living patients is 46 months (range, 13-103).Thirty seven (22%) patients had evidence of MRD (13 by flow cytometry only, 17 by cytogenetics/FISH only and 7 by both). MRD was more common in patients with poor risk karyotype at diagnosis and CRi at the time of allo-HCT (Table 1). PFS (P= 0.0016), OS (P=0.002), and CIR (P=0.02) were all significantly worse in MRD+ patients (Figures 1& 2). In univariate analysis, MRD+ patients, assessed by flow cytometry had worse PFS (P=0.0216) and OS (P=0.0314) compared to MRD- patients. Similarly patients with evidence of MRD+ by cytogenetics/FISH had worse PFS (P=0.007) and OS (P=0.0031). In a multivariate cox proportional hazards model 1) any MRD positivity prior to allo-HCT, 2) poor-risk karyotype at diagnosis, and 3) CRi at allo-HCT independently predicted significantly poor PFS and OS. Only poor-risk karyotype was associated with a significant increase in CIR, while MRD positivity showed a trend towards higher CIR. Conclusion: MRD positivity prior to HCT by either flow cytometry or by cytogenetics/FISH independently predicts adverse AML outcomes. Table 1. Comparison of pre-transplant variables Covariate Label MRD + (N=37) MRD - (N=129) P-Value Age(years) < 40 8 (21%) 20 (16%) 0.708 40 - 59 20 (53%) 69 (54%) ≥ 60 10 (26%) 39 (30%) Karyotype risk Favorable/ Intermediate 19 (53%) 95 (74%) 0.011 Poor 18 (47%) 33 (26%) Timing of Allo-HCT 1st remission (CR1) 28 (74%) 97 (76%) 0.792 > CR1 10 (26%) 31 (24%) Allo-HCT after1st relapse(>CR1): duration of CR1 > 12 mo 31 (82%) 113 (88%) 0.285 ≤ 12 mo 7 (18%) 15 (12%) Secondary AML No 23 (60%) 78 (61%) 0.964 Yes 15 (40%) 50 (39%) Complete remission vs CRi CR 28 (74%) 110 (86%) 0.077 CRi 10 (26%) 18 (14%) Conditioning Regimen Ablative 24 (63%) 72 (56%) 0.449 Other 14 (37%) 56 (44%) Donor Type Matched sibling donor 12 (32%) 42 (33%) 0.887 Other 26 (68%) 86 (67%) Female donor: male recipient (FDMR) Other 28 (80%) 91 (78%) 0.844 FDMR 7 (20%) 25 (22%) Disclosures No relevant conflicts of interest to declare.

Sign in / Sign up

Export Citation Format

Share Document