Blood and Marrow Transplantation (BMT) in Acute Leukemia Patients in Cuba: Current Results and Future Opportunities through International Collaboration

Abstract In the majority of low-middle-income countries (LMIC) worldwide, cancer care is limited by lack of patients' access to care and/or unaffordable cost of treatment. In contrast with many other LMIC, Cuban government provides cancer therapy to every citizen. Therefore, any standard treatment for acute leukemias, including BMT, is available for free. However, because of limited financial resources laboratories do not always provide immunophenotypic, cytogenetic or molecular tests to support the diagnosis or the management of leukemias, and only standard chemotherapy protocols are available. In this retrospective study we analyzed the results of BMT in adult acute leukemia patients transplanted at the Hermanos Ameijeiras Hospital in Havana (Cuba) from June 1986 to January 2016. A total of 101 consecutive cases (83 acute myeloid leukemia [AML] and 18 acute lymphoblastic leukemia [ALL]) were transplanted. Eligibility criteria for BMT included: age >16 and <60; achievement of morphologic complete remission after induction and consolidation chemotherapy and no severe comorbidities according to standard BMT criteria. Because of lack of access to international donor registries, only patients who had an HLA matched related donor (MRD) received an allogeneic BMT, whereas the others received a further consolidation with an autologous BMT. Stem cell source was fresh bone marrow in 80% of patients, fresh G-CSF mobilized peripheral blood (PBSC) in 19%, and only 1 cord blood transplant was attempted in a patient without a MRD. Of 83 AML patients, 36 received an allogeneic (AML-allo) and 47 an autologous (AML-auto) stem cell transplant. Median age in AML-allo and AML-auto groups was 37 (range:22-54) and 36 (range: 18-58) years, respectively. Median follow-up was 50.4 months (range:1-288) in AML-allo and 50.7 months (range: 1-324) in AML-auto. This is in part due to the policy that patients from outside Havana return to their primary hematologist within 1-2 years after transplant. In addition, some patients left Cuba soon after transplant. Of 36 AML-allo 36% died of transplant-related-mortality (TRM) and 25% of relapse. On the contrary, of 47 AML-auto 17% died of TRM and 40% of relapse. Overall survival (OS) was 38% in AML-allo and 42% in AML-auto. Of 18 ALL patients, 7 received an allogeneic (ALL-allo) and 11 and autologous (ALL-auto) transplant. Median age in the two groups was 36 (range: 18-47) and 27 (range:17-34) years, respectively. Of 7 ALL-allo cases, 1 died of TRM and 3 of relapse (OS 43%). Of 11 ALL-auto cases 4 patients died, all due to relapse (OS 64%). In conclusion, BMT is available for acute leukemia patients in Cuba. Despite limited resources, we envision that through an active collaboration with UIC the BMT program at the Hermanos Ameijeiras Hospital may rapidly expand its activity by developing disease risk assessment through cytogenetic and molecular technologies, implementing cryopreservation of stem cells from PBSC, introducing haploidentical transplantation for patients without a MRD, offering reduced intensity conditioning regimens to patients >60 years old. Support of training and development of research infrastructures remain of key importance in global health cancer care and global BMT. Disclosures No relevant conflicts of interest to declare.

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Characterization of Thy-1 (CDw90) expression in CD34+ acute leukemia

Blood ◽

10.1182/blood.v86.1.60.bloodjournal86160 ◽

1995 ◽

Vol 86 (1) ◽

pp. 60-65 ◽

Cited By ~ 14

Author(s):

JT Holden ◽

RB Geller ◽

DC Farhi ◽

HK Holland ◽

LL Stempora ◽

...

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Stem Cell ◽

Acute Leukemia ◽

Lymphoblastic Leukemia ◽

Blast Crisis ◽

Myelogenous Leukemia ◽

Acute Leukemias ◽

Hematopoietic Stem

Thy-1 (CDw90) is a phosphatidylinositol-anchored cell surface molecule which, when coexpressed with CD34 in normal human bone marrow, identifies a population of immature cells that includes putative hematopoietic stem cells. To date, the characterization of Thy-1 expression has been confined largely to normal tissues and cell lines. In this study, we evaluated the frequency and intensity of Thy-1 expression as defined by reactivity with the anti-Thy-1 antibody 5E10 in 38 cases of CD34+ acute leukemia (21 acute myelogenous leukemia [AML], 8 chronic myelogenous leukemia [CML] in blast crisis, and 9 acute lymphoblastic leukemia [ALL]). In 34 of 38 cases (89%) the CD34+ cells lacked expression of the Thy-1 antigen. High-density Thy-1 expression was found in 1 case of CML in lymphoid blast crisis, and low- density Thy-1 expression was identified on a portion of the leukemic cells in 2 cases of AML with myelodysplastic features, and 1 case of CML in myeloid blast crisis, suggesting a possible correlation between Thy-1 expression and certain instances of stem cell disorders such as CML and AML with dysplastic features. In contrast, the dissociation of Thy-1 and CD34 expression in the majority of acute leukemias studied suggests that the development of these leukemias occurs at a later stage than the hematopoietic stem cell. Characterization of Thy-1 expression in acute leukemia may eventually provide insights into the origin of the disease. In addition, separation of leukemic blasts from normal stem cells based on Thy-1 expression may prove useful in assessing residual disease, as well as in excluding leukemic blasts from stem cell preparations destined for autologous bone marrow or peripheral stem cell transplantation.

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Incidence of Venothromboembolism (VTE) in Patients (pts) with Acute Lymphocytic Leukemia (ALL), Burkitt’s Leukemia/Lymphoma (BL) or Lymphoblastic Leukemia (LL).

Blood ◽

10.1182/blood.v108.11.4534.4534 ◽

2006 ◽

Vol 108 (11) ◽

pp. 4534-4534

Author(s):

Khanh D. Vu ◽

Deborah A. Thomas ◽

Julie C. Hubbard ◽

Stefan Faderl ◽

Jorge Cortes ◽

...

Keyword(s):

Acute Leukemia ◽

Upper Extremity ◽

Lymphoblastic Leukemia ◽

Bleeding Complications ◽

Cell Transplant ◽

Thromboembolic Events ◽

Maintenance Chemotherapy ◽

Acute Leukemias ◽

Vte Prophylaxis ◽

Increased Risk

Abstract Background: Pts with cancer are at increased risk of thromboembolic events with potentially life-threatening consequences. The incidence of VTE in cancer pts has been estimated at 1 in 250. Although most of these episodes are associated with solid tumors, VTE is also observed in pts with acute leukemias, even in the presence of thrombocytopenia. Anticoagulation in this pt population can be particularly problematic if pts are undergoing myelosuppressive chemotherapy. VTE prophylaxis is often not given because of the perceived high risk of bleeding with a presumed low risk of VTE. Method: As little is known about the incidence and significance of VTE in pts with acute leukemia, we conducted a retrospective chart review of 223 pts with ALL, BL, or LL who received a hyper-CVAD regimen (fractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone alternating with methotrexate and cytarabine) with or without rituximab, maintenance chemotherapy (with L-asparaginase only months #7 & 18), allogeneic stem cell transplant (SCT), or salvage chemotherapy at our institution from November 1999 to May 2005. The median observation period was 112 weeks (range 1–328). Results: The median age was 51 yrs (range 19–75). 70% were ALL, (50% were Philadelphia positive ALL), 20% Burkitt’s or Burkitt’s-like, and 10% LL. Thirty nine of 223 pts (18%) had confirmed VTE by imaging studies: 12.5% prior to or at the time of diagnosis, 57.5% during consolidation chemotherapy, and 27.5% during maintenance chemotherapy, SCT, or supportive care. Location of VTE varied by site: 3/39 (8%) pulmonary embolus, 16/39 (41%) lower extremity, 2/39 (5%) central venous catheter (CVC), and 18/39 (46%) upper extremity. Two of the 18 with upper extremity VTEs did not have CVC, and an additional 2 had bilateral upper extremity thromboses. The platelet counts were reviewed near the time of VTE diagnosis: 22/39 (56%) had greater than 100 × 109/L, 17/39 (44%) were less than that value, with 76% below 50,000 × 109/L. Conclusion: Pts with ALL, BL, and LL undergoing therapy are at risk for developing VTE. Thrombocytopenia does not preclude development of VTE. A more detailed analysis will be forthcoming regarding the risk factors for VTE in this pt population, the current medical practices and bleeding complications with VTE prophylaxis and treatment, and the effect on therapy administration and overall survival. Practice guidelines for management of acute leukemia pts with thromboembolic events should be pursued.

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Impact of Rapid Lymphocyte and Monocyte Recovery on Overall Survival Post-Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) with Fludarabine/Melphalan Conditioning

Blood ◽

10.1182/blood.v118.21.3040.3040 ◽

2011 ◽

Vol 118 (21) ◽

pp. 3040-3040

Author(s):

Lori DeCook ◽

Mary Thoma ◽

Tanya Huneke ◽

Nicole Johnson ◽

Robert Wiegand ◽

...

Keyword(s):

Overall Survival ◽

Stem Cell ◽

Acute Leukemia ◽

Hematopoietic Stem Cell ◽

Conflicts Of Interest ◽

Positive Impact ◽

Cell Transplant ◽

Hematopoietic Stem ◽

Absolute Lymphocyte Counts ◽

Complete Blood Counts

Abstract Abstract 3040 We have previously shown that both lymphocyte and monocyte recovery are strongly associated with improved survival post-myeloablative allogeneic hematopoietic stem cell transplant for acute leukemia (Thoma et al, Biology of Blood and Marrow Transplantation, in press). We hypothesized that rapid lymphocyte and monocyte recovery would have a similarly positive impact on overall survival in reduced intensity conditioning (RIC) HSCT with fludarabine/melphalan. To test our hypothesis, we analyzed 118 consecutive patients who underwent allogeneic HSCT with fludarabine/melphalan conditioning for AML (n=49) and MDS/MPN (n=38), ALL (n=7) and other lymphoid malignancies (n=24) at our institution from 2001–2010. The absolute lymphocyte counts and monocyte counts (ALC and AMC, respectively) derived from routine complete blood counts were determined longitudinally at days +15, +30, +60, +100 and correlated with clinical outcomes. At the day +30 time point, both ALC and AMC > 0.3 × 10(9) cells/L were strongly associated with improved survival (OS 29.6 months vs. 5.4 months, p=0.006 and 25.3 months vs. 5.1 months, p=0.01 respectively), a pattern that continued through the day +100 evaluation. Multivariate analysis including age, CD34+ cell dose, unrelated vs. related HSCT, presence of aGVHD, remission status, and longitudinal hematologic parameters revealed that day +100 ALC (RR 0.21, 95% CI 0.07–0.66, p= 0.0096) and day +100 AMC (RR 0.41, 95% CI 0.2–0.9, p=0.047) were the only independent predictors of survival in the model. Pairwise correlations showed moderate negative associations between aGVHD and day +60 and day +100 ALC and AMC. To further explore whether any inherent patterns in the timing of lymphocyte and monocyte recovery had prognostic value post-HSCT, we performed unsupervised hierarchical clustering on the longitudinal hematopoietic parameters studied in this cohort and identified four clusters of patients, clusters A-D. Patient clusters A and C both demonstrated improved ALC and AMC recovery at the day +60 and day +100 time points and had significantly improved OS compared with clusters B and D (not reached for A and C vs. 54.9 and 22.3 months, respectively, p<0.001). No patient in cluster D had a day +100 AMC > 0.3 × 10(9) cells/L, and these patients experienced more acute GVHD (p=0.006) and relapse (8 of 14 patients, p=0.002) compared with clusters A, B, and C (p=0.002). 29 patients who were unable to be clustered with this algorithm, predominantly due to early toxic deaths, had a median survival of 6 months. Consistent with previous observations in our myeloablative cohort, both lymphocyte and monocyte recovery are predictive of overall survival post-RIC HSCT. However, compared to the myeloablative cohort, monocyte recovery in this series appears slightly less strongly associated with survival. Our results also extend the observation of improved survival of ALC and AMC recovery post-HSCT to diseases beyond acute leukemia. Disclosures: No relevant conflicts of interest to declare.

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Low Prevalence of T-Cell Lymphoblastic Leukemia/Lymphoma in an Adult Hispanic Population: A Report of the Acute Leukemia Working Group (GTLA)

Blood ◽

10.1182/blood-2020-142639 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 5-6

Author(s):

Luis Felipe Rubalcava-Lara ◽

Emmanuel Almanza Huante ◽

Roberta Demichelis ◽

Juan Rangel-Patiño ◽

Andres Gomez-De Leon ◽

...

Keyword(s):

T Cell ◽

Acute Leukemia ◽

Conflicts Of Interest ◽

Lymphoblastic Leukemia ◽

Univariate Analysis ◽

Rank Test ◽

Induction Treatment ◽

P Value ◽

Cell Transplant ◽

Hispanic Population

Introduction: The proportion of Acute lymphoblastic T cell leukemia/lymphoma (T-ALL/LBL) in Latinamerica (LA) is about 13% [Quiroz, 2018], compared with 25% of other publications [Litzow,2015]. In the largest leukemia series of adult Mexican population, the incidence of T-ALL was merely 2.9% with a -SG. The main objective of this study was to describe the epidemiological characteristic and survival of T-ALL in 4 reference oncology centers in Mexico. Methods: Retrospective cohort study from 2014 to 2019 in all consecutive, newly diagnosed T-ALL patients defined by flow cytometry (FC). The primary end point was to assess the survival of T-ALL in a Hispanic population. Baseline characteristics were grouped in tables and summarized as medians and ranges. Sub-groups were compared using chi-square test for binary variables and Mann-Whitney U test for quantitative variables. The Overall Survival (OS) analysis was made using Kaplan-Meier curves and comparison between groups was performed using the log-rank test with a significant P value less than 0.05 with 95% confidence interval. Results: A total of 47 patients were identified, which represent 11.1% of all acute leukemia the median of age was 30 years. The 83.7% being identified in the adolescent young-adult (AYA) group. Counterintuitively a 44.9% had a previous comorbidity (diabetes, hypertension, dyslipidemia) considering the range of age. The 85% had a low risk of mortality using the modified Charlson index, the median count of leukocytes was 36 x 109 (range 6.78-117) and 28% presented with initial hyperleukocytosis, the median LDH was 605 UI/l (range 343-1451). Applying the European Group for the Immunological Classification of Leukemias criteria: 28% were cortical T, 41.7% were mature and approximately 30% were be classified as early. Applying the early T-P (ETP) definition a total of 10 cases were identified (22.2% prevalence). The use of hyperCVAD and pediatric inspired regimens shared the same rate (41.3%), strikingly there is still a 17.4% of patients that received other type of chemotherapy for diverse reasons (economic, shortage of treatment, patient or physician preference) being the CHOP-inspired schemes the most used. The rate of complete response (CR) at 4 weeks after induction was 68.2% with 54.2% having a negative minimal residual disease (MRD). After 8 weeks a total of 34 (77.3%) patients achieved CR, with 63.6% and 66.7 % maintaining negative MRD at 16 weeks and after consolidations, respectively. Only 38.3% were able to complete the full induction treatment without a dose adjustment due to toxicity. A total of 8 (19.5%) were refractory to initial frontline treatment and eventually 23 (60.5%) relapsed, with a total of 10 patients presenting with CNS infiltration at relapse. A total of 6 patients received an allogenic stem cell transplant (ASCT), with 4 of them being alive and in CR at the 100 days cutoff. The median OS was 16 months (CI 95% 11.4-21.09) and 38.8% of our population was alive at the 24 months cutoff. This time period was drastically reduced for the non-AYA population who had a OS of 7.69 months (CI 95% 0-21.24) and 21.9% a 24 months progression free survival (PFS), compared with 16.6 months (CI 7.41-25.81) and 41.6% 24 months PFS. In the univariate analysis refractoriness to induction (p 0.039) and higher number of cycles (p 0.02) were associated with worse outcome. Conclusions: The T-ALL predominantly affects AYA populations while its incidence in our country appears to be lower even in large oncologic concentration centers. The proportion of ETP was slightly higher than that reported in other studies. Lower CR rates with a low frequency of ASCT in comparison to those reported in high income countries was observed, probably associated with the delay in implementation of pediatric-inspired regimens and lack of access to ASCT. Disclosures No relevant conflicts of interest to declare.

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Matched Cohort Analysis of Allogeneic Hematopoietic Cell Transplantation (HCT) with Total Marrow Irradiation/Fludarabine/Melphalan (TFM) Versus Fludarabine/Melphalan (FM) Conditioning for Acute Leukemia

Blood ◽

10.1182/blood.v120.21.222.222 ◽

2012 ◽

Vol 120 (21) ◽

pp. 222-222 ◽

Cited By ~ 1

Author(s):

Joseph Rosenthal ◽

Jefrrey Wong ◽

Anthony Selwyn Stein ◽

Tracy Stiller ◽

Joycelynne Palmer ◽

...

Keyword(s):

Acute Leukemia ◽

Hematopoietic Cell Transplantation ◽

Disease Risk ◽

Conflicts Of Interest ◽

Chronic Gvhd ◽

Cohort Analysis ◽

Unrelated Donor ◽

Eligibility Criteria ◽

Total Marrow Irradiation ◽

Grade 3

Abstract Abstract 222 We have previously reported the feasibility and safety of augmenting the reduced-intensity regimen (RIC) of FM by addition of total marrow irradiation, a targeted form of TBI, using a helical tomotherapy (HT) device (Rosenthal, Blood. 2011;117(1):309–315). In this study we compared outcomes in patients with acute leukemia undergoing HCT receiving either TFM or FM. Patients and Methods: We analyzed 72 patients with acute leukemia or MDS who received either FM (N=36) or TFM (N=36) HCT. Eligibility criteria for TFM were age > 50 years of age or compromised organ function (COF); high-risk remission or marrow blasts ≤10%. TFM patients were matched to a set of FM patients based on age, gender, diagnosis and disease risk (low, intermediate, high). All patients received FM with fludarabine 25 mg/m2/d × 5 days and melphalan140 mg/m2/d × 1 day, and TMI was delivered at 150cGy/fraction in 8 fractions over 4 days in the TFM group. Supportive care and treatment for prevention of GVHD were given according to our institution standard guidelines for both groups. Results: Demographic characteristics were similar, including gender (20 females, 55.6%) and age (median 58 years, range: 22–68 in TFM and 20–68 in FM). The proportions of patients by diagnoses were similar: AML (n=27), ALL (n=7), MDS (n=2). Disease risk assignments in both groups were: Low risk (n=15), intermediate (n=6), high (n=15). There were 15 and 13 pts with active disease in FM and TFM, respectively. HLA-identical siblings (n=16, 44.4%) or matched unrelated donor (n=20, 55.6%) were used in each group. Outcomes are reported for the TFM and FM recipients, respectively as follows: myeloid recovery was documented on day 13.5 (9–24) and 15 (8–20). Transplant-related toxicities were limited to grade 3 or less in both groups. The most common grade 3 toxicities were: mucositis, n=9 and n=7 and bacterial infection, n=10 and n=11, respectively. Acute GvHD grade II-IV occurred in 20 pts (55%) and 19 (53%). Extensive chronic GVHD was documented in 24 (67%) and 20 (56%) pts. Twenty-one and 18 patients are alive at a median of 30.2 months and 35.3 months in the TFM and FM, respectively. The relapse cumulative incidence at 2 years post HCT was 11.1% (TFM) compared to 30.6% (FM) (p=0.06) (insert ). With a median follow-up of 31.7 months (4.1 – 62.5) for alive patients, the 2-year overall and progression-free survival estimates are 57.2 % (95% CI, 46.6–66.4) -TFM, and 62.8% (95% CI, 51.8–72.0) -FM, and 57.7% (95% CI, 47.2–67.0) -TFM, and 48.5% (95% CI, 40.2–56.3) -FM, respectively. Conclusion: The addition of TMI at a dose of 1200 cGy to FM is safe and tolerable and may decrease the risk of relapse related mortality. Disclosures: No relevant conflicts of interest to declare.

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Infectious Complications in Acute Leukemia, Experience in a Public Institution in Mexico

Blood ◽

10.1182/blood.v126.23.4902.4902 ◽

2015 ◽

Vol 126 (23) ◽

pp. 4902-4902

Author(s):

Nidia P. Zapata ◽

Jorge Carlos Torres ◽

Ramiro Espinoza ◽

Eduardo Cervera

Keyword(s):

Septic Shock ◽

Acute Leukemia ◽

Conflicts Of Interest ◽

Lymphoblastic Leukemia ◽

Infectious Complications ◽

Causal Agent ◽

Public Institution ◽

Intensive Chemotherapy ◽

Acute Leukemias ◽

Electronic File

Abstract Infectious complications are a major cause of morbidity and mortality in hematologic patients with acute leukemia. In this paper we address the mayor infectious complications, at the Leukemia Clinic (LC) in the Instituto Nacional de Cancerologia (INCan) Material and Methods. This is a retrospective, observational study, carried on at INCan. We included all patients that attended the LC and died of an infectious complication between January 2012 and December 2014, regardless of status (new case/relapsed) at diagnosis, we included patients with Acute Lymphoblastic Leukemia (ALL), Acute Myeloid Leukemia (AML), Acute Biphenotypic Leukemia (ABL) and Acute Promyelocytic Leukemia (APML). The main objective of the study was to determine the most frequent causes of infectious complications in the treatment of acute leukemias. Results. We included 240 patients that were admitted to the LC between the study dates. 12 patients were excluded since they were later diagnosed with another hematologic malignancy rather than leukemia. 228 patients were analyzed. 132 males, 96 females, 36 years was the median age (14-85 years). 126 patients were new cases and 102 patients were treated for relapse. AML 69 patients, ALL 140 patients, ABL 9 patients, and APML 10 patients. We revised the data of all the deaths that occurred in the period of time. 100 cases were included in the study, of those, 30 that were not infectious related and were excluded. Of the 40 patients included, 41 were males and 29 females, with a mean age of 36.8 years (16-72). 44 ALL patients, 18 AML patients, 7 ABL patients and 1 APML patient. 32 patients were new cases and 38 were relapses. The media number of relapses was 1 (1-3). Septic Shock was stated as the cause of death on all electronic files, with Pneumonia as the most common cause of infection origin with 47 patients. As for determining the causal agent of the infection, we used the last positive culture 5 days prior to the death, we found a causal agent in only 47 patients; the most frequent agents involved were: Escherichia coli BLEE with 13 patients, Enterococus faecium with 6 patients, we also report 1 H1N1 and 1 H3N2 influenza infections. 14 patients did not received intensive chemotherapy prior to death, 11 were on supportive care, and 3 of them did not consent treatment. HyperCVAD was the most frequent regimen administered prior to death, with 13 patients, 7+3 followed with 11 patients. POMP in the setting of palliative regimen was also prevalent with 12 patients. 52% of the patients were in nadir of chemotherapy, with a mean of days of 19 (3-64). All patients that received intensive chemotherapy received GSFC and meropenem/vancomycin regimen once septic shock was diagnosed according to the data in the electronic file. All patients received treatment in the beginning, of the 70 patients only 19 were treated in the intensive care unit (ICU). Conclusions. We addressed the most frequent causes of infectious complications at the Acute Leukemia Clinic, as we thought, E. coli BLEE was the most frequent agent involved, perhaps diverting from reports in the literature, we have a low prevalence of gram positive cocci. Pneumonia is the most frequent site of infection, all our patients are admitted to for chemotherapy, hence all the pneumonia cases are hospital acquired. POMP is a prevalent regimen reported, since we use this regimen for palliative care we could relate mortality to relapse/refractory disease more than to toxicity itself. No maintenance regimens were reported in the results. Our study has certain limitations, no mycotic infections could be reported as the electronic file lacks reliable information. Disclosures No relevant conflicts of interest to declare.

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Unmanipulated Graft Transplantation From Family Haploidentical Donors: A Survey On 183 Adult Patients with Acute Leukemias On Behalf of the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT)

Blood ◽

10.1182/blood.v120.21.1987.1987 ◽

2012 ◽

Vol 120 (21) ◽

pp. 1987-1987

Author(s):

Fabio Ciceri ◽

Myriam Labopin ◽

Paolo Di Bartolomeo ◽

William Arcese ◽

Stella Santarone ◽

...

Keyword(s):

Multivariate Analysis ◽

High Risk ◽

Acute Leukemia ◽

Advanced Disease ◽

Conflicts Of Interest ◽

Lymphoblastic Leukemia ◽

Conditioning Regimen ◽

Treatment Algorithm ◽

Working Party ◽

Acute Leukemias

Abstract Abstract 1987 Background. Allogeneic stem cell transplantation from an haploidentical family donor has been recently developed through unmanipulated graft platforms. Methods. We collected in 57 EBMT centers 183 haploidentical transplants (haploSCT) from unmanipulated peripheral blood (PB) and bone marrow (BM) graft in adults patients (pts) with de novo acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) reported to EBMT registry from 2007 to 2010 and analysed the outcome according to the known risk factors. Results. Overall, 120 AML patients underwent transplantation in CR1 (39), CR2 (22) or in advanced disease (54). Overall, 63 ALL pts underwent transplantation in CR1 (26), CR2 (14) or in advanced disease (22). Median age was 42y (18–75). Graft composition was based on non ex-vivo T-cell depleted BM in 52 (28%) or PB in 131 (72%). Conditioning regimen was myeloablative (MAC) in 95 and reduced-intensity (RIC) in 88 pts. Primary engraftment was documented in 160 pts (88%), with ANC 0.5 ×109/L in a median of 19 days (BM) and 16 days (PB). Graft-versus-Host Disease (GvHD) prophylaxis was based on Anti-thymocyte globulins (ATG) + cyclosporine-methotrexate (24%) or cyclosporine-mycophenolate (18%), rapamycine-mycophenolate (25%), tacrolimus-mycophenolate (15%), others (7%). The cumulative incidence of acute GvHD >=II was 26%. With a median follow-up of 13 months (1–49), the estimated leukemia-free survival (LFS) at 1 years i was 53 +/−7%, 36 +/−8% and 22 +/−5% for CR1, CR2 and advanced patients respectively. In multivariate analysis for competing risks, relapse incidence (RI) at 1 y was 23 +/−5%, 20 +/−7%, 48 +/−6% for CR1, CR2 and advanced. The non-relapse mortality (NRM) at 1 y was 23 +/−6%, 43 +/−5%, 29 +/−6% for CR1, CR2 and advanced patients. On multivariate analysis, the only factor relevant for LFS was disease status at transplant. Conclusion. EBMT registry analysis of haploidentical transplantation from unmanipulated donor graft confirms relevant LFS for patients with high risk acute leukemia. These results suggest that this procedure should be considered prospectively int treatment algorithm for high risk adults patients in early stages. Disclosures: No relevant conflicts of interest to declare.

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T Cell Depleted Allogeneic Stem Cell Transplants for Hematological Malignancies: A 20 Year Experience Shows No Relationship Between Choice of Transplanted T Cell Dose or Delayed T Cell Add-Back on Major Outcomes

Blood ◽

10.1182/blood.v126.23.2013.2013 ◽

2015 ◽

Vol 126 (23) ◽

pp. 2013-2013

Author(s):

Prathima Anandi ◽

Xin Tian ◽

Puja D. Chokshi ◽

Noelle Watters ◽

Sawa Ito ◽

...

Keyword(s):

Stem Cell ◽

T Cell ◽

Disease Risk ◽

Conflicts Of Interest ◽

Chronic Gvhd ◽

Cell Depletion ◽

Cell Transplant ◽

T Cell Depletion ◽

Cell Dose ◽

Increased Risk

Abstract Introduction: T cell depletion of the stem cell allotransplant (SCT) has the advantage of reducing incidence and severity of GVHD but can be complicated by relapse and infection. An optimum residual T cell dose in T depleted SCT is not known. To optimize T cell depletion we delivered a series of fixed T cell transplant doses with scheduled T cell add back post-SCT in a series of protocols to determine the T cell doses that secured immune reconstitution, and minimized relapse and infection. Here we retrospectively examined large series of patients (pts) transplanted in a single institution where T cell dose at SCT and add back were quantitated. Unique to these protocols was the precise measurement of CD3 dose/kg at transplant for every patient which enabled us to relate transplant T cell doses to outcome. Patients and methods: 205 pts (106 males, 99 females) underwent HLA identical sibling allogeneic T cell depleted SCT between 1994 and 2014. Diagnosis at SCT included AML (48%), MDS (17%), ALL (27%), CLL (5%), MM (3%). Disease risk at SCT was classified as high (57%) or standard (43%). The median age at SCT was 37 (range: 10-75) yrs. TBI based myeloablative conditioning was used. The graft source was marrow in 20 pts and peripheral blood in 195 pts. GVHD prophylaxis was low dose cyclosporine. Different T cell depleted methods were used consecutively: elutriation, Isolex ®, Cellpro ® CD34, and Miltenyl © CD34 selection. A defined T cell dose was allocated at SCT by protocol ranging from 2 - 50 × 104 CD3+ cells/kg. Various schedules were used to add back T lymphocytes between day 30 to 90 with doses ranging 5 - 60 ×106 CD3+ cells/kg by protocol and no T cell add-back was given in 28 pts in recent protocols. Overall survival (OS) was estimated by the Kaplan-Meier method, and cumulative incidence of relapse and nonrelapse mortality (NRM) was estimated by Gray's method to account for competing risks. Cox proportional hazard regression models were used to assess the association of factors at baseline, day 100 and GVHD with the post-SCT outcomes. Results: At a median follow-up of 8.6 yrs (range: 0.7- 19.8) for surviving pts, 112 pts died (52 from NRM) and 68 pts relapsed. OS was 47%, 43% and 41%, NRM was 24%, 27% and 27%, relapse was 32%, 34% and 38% at 5 yr, 10 yr and 15 yr post SCT, respectively. Grade II-IV and III-IV acute GVHD were 41% and 13%, and chronic GVHD was 42% (25% limited, 17% extensive). In the multivariate models of baseline risk factors that adjusted for age at SCT and disease risk, T-cell doses at SCT did not affect OS, NRM or relapse. A higher dose of CD34+ cells at SCT was significantly associated with better OS and lower NRM. Disease risk was an independent predictor, with high-risk pts having more relapse and worse OS, compared to pts with standard risk. A landmark analysis of 156 pts surviving and relapse-free beyond day 100 was carried out to examine the effects of add back T cell schedules by day 100 and aGVHD. The total T-cell dose at add back by day 100 and different add-back T-cell schedules from day 30-90 had no impact on any outcome, controlling for T-cell dose at SCT. In the models controlling for age, risk, CD34+ and T-cell dose at SCT, pts with grade III-IV aGVHD by day 100 had an increased risk for overall mortality and NRM beyond day 100 (HR= 3 and 3.6, both P<0.001), but did not affect relapse. An analysis of pts surviving and relapse-free beyond 1 yr showed pts with extensive cGVHD had higher NRM rate (39%) and lower relapse rate (0%) after 1 yr post-HSCT compared to pts with no cGVHD ( NRM, 9%, P = 0.020; relapse 24%, P=0.026). Conclusion: These findings indicate that for myeloablative matched sibling SCT there is no ideal prescription of T cell dose at transplant within a range of 104 - 105 or for scheduled add back of lymphocytes within a range of T depletion 5 - 60 × 106. Instead, factors other than T cell dose either at transplant or when add-back was delayed determined GVHD incidence, relapse, and survival. These findings set a limit on the efficacy of any T cell depletion procedure to optimize transplant outcome. Disclosures No relevant conflicts of interest to declare.

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Association of Janus Kinase 2(JAK2) A830G Polymorphism with Acute Leukemia Susceptibility.

Blood ◽

10.1182/blood.v114.22.1573.1573 ◽

2009 ◽

Vol 114 (22) ◽

pp. 1573-1573

Author(s):

Bao-An Chen ◽

Yue-Jiao Zhong ◽

Ji-feng Feng ◽

Yu-feng Li ◽

Jia-Hua Ding ◽

...

Keyword(s):

Logistic Regression ◽

Acute Leukemia ◽

Genomic Dna ◽

Conflicts Of Interest ◽

Lymphoblastic Leukemia ◽

Janus Kinase ◽

Regression Analyses ◽

Chi Square ◽

Acute Leukemias ◽

Flight Mass Spectrometry

Abstract Abstract 1573 Poster Board I-599 Background Aberrant activation of the The Janus kinase(JAK)/signal transducer and activator of transcription (STAT) pathway may predispose to leukemia cells due to deregulation of proliferation, differentiation or apoptosis. One of the members of this family, JAK2, plays a very important role in metabolizing carcinogens and medications. In this study, we aimed to determine whether any association exists between genetic polymorphism in JAK2 A830G and individual susceptibility to acute leukemia. Method We carried out a case-control study using a China sample set with 243 acute leukemia cases and 282 controls matched by age, ethnicity. 68 of the acute leukemia patients were diagnosed with acute lymphoblastic leukemia (ALL) and 175 patients with acute myeloid leukemia (AML). Genomic DNA was isolated from peripheral blood and genomic DNA samples were assayed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF) in the A830G on JAK2 gene. The data were analyzed statistically employing chi-square and logistic regression analyses. Result The frequencies of G/G genotype (wild type) were 4%, 8% and 31.4% in ALL, AML and control groups, respectively. The frequencies of polymorphic G/A genotype (heterozygous variant) were found to be 69% in ALL patients, 71% in AML patients and 48.6% in controls. The A/A genotype (homozygous variant) were existed to be 69% in ALL patients, 20% in AML patients and 20% in controls. Logistic regression analyses showed a significant correlation between the JAK2 A830G polymorphism (G/G) and acute leukemia patients (OR = 1.309, 95% CI =0.839-2.043, p<0.001). Conclusion Our findings indicate that G/G genotype may be an important genetic determinant for acute leukemias. According to our knowledge, this is the first report of an association between acute leukemia cases and the JAK2 A830G polymorphism. Disclosures No relevant conflicts of interest to declare.

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Phase I Trial of the Oral Poly (ADP-ribose) Polymerase (PARP) Inhibitor Veliparib (ABT-888, V) Combined Wtih Topoecan (T) and Carboplatin (C) for Adults with Relapsed and Refractory Acute Leukemias

Blood ◽

10.1182/blood.v116.21.3276.3276 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3276-3276

Author(s):

Judith E. Karp ◽

Keith W Pratz ◽

Mark R. Litzow ◽

Jiuping Ji ◽

Alice Chen ◽

...

Keyword(s):

Stem Cell ◽

Phase I ◽

Dose Escalation ◽

Lymphoblastic Leukemia ◽

Parp Inhibitor ◽

Myelogenous Leukemia ◽

Hematologic Toxicity ◽

Cell Transplant ◽

Nuclear Staining ◽

Acute Leukemias

Abstract Abstract 3276 PARP is activated in response to DNA single strand (SS) breaks and is pivotal to the base excisional repair pathway for chemotherapy-damaged DNA. The orally bioavailable PARP inhibitor V delays DNA repair and potentiates the cytotoxicity of multiple classes of chemotherapy drugs including topoisomerase I inhibitors and platinating agents in leukemia cell lines. A previous clinical trial of T+C yielded promising results in adults with refractory acute leukemia at the maximum tolerated dose (MTD) of T 1.6 mg/m2/d + C 150 mg/m2/d by intravenous continuous infusion (IVCI) × 120 hrs. We are conducting a Phase I dose-escalation trial of V given orally twice daily Days 1–8 with T+C given by 120 hr IVCI Days 3–7. Acute Myelogenous Leukemia (AML, 33 patients) Acute Lymphoblastic Leukemia (ALL, 4 patients) Median Age (range) 570 (40-75) 55 (42-62) Relapsed 8 No. Prior CRs 2 (1-3) Prior Stem Cell Transplant 2 0 Refractory 25 4 No. Primary Refractory 10 1 No. Prior Regimens 3 (1-4) 3 (1-4) Prior Stem Cell Tranpslant 3 1 Secondary AML 12 Anecedent Hematologic Dx 6 Treatment-Related 6 Cytogenetics Intermediate 10 2 Adverse: Single/Complex 7/16 2 Ph+ (1 with complex) BRCA-1/BRCA-2 1 (mutation)/ 1 (13q14 deletion) 0 Deaths due to myocardial infarct and splenic infarcts with ascites occurred in one pt each when C 150 mg/m2 was added to V 10 mg BID and T 1.3 mg/m2, resulting in adjustment of the dose escalation schema for C and T. Of 27 pts treated at doses of V 10–20 mg orally BID Days1-8 and T 1.0–1.2 mg/m2/d + C 120–150 mg/m2/d for 120 hrs IVCI Days 3–7, 8 (30%) have experienced > grade 3 non-hematologic toxicity, 4 (15%) have had grade 4 toxicity and 1 (4%) died from sepsis with multi-organ failure. Overall response rate is 22% (2 CR, 1 CRi, 3 PR), with 4 in relapsed AML, 1 each in refractory AML and refractory ALL. Pharmacokinetic (PK) studies in pt plasma, marrow supernatant, and marrow blasts demonstrated that V does not accumulate with multiple dose administrations in plasma but does in marrow, is not altered by T or C administration, and is detectable in marrow supernatant and cells. Nuclear staining for phosphorylated histone H2AX (γH2AX) demonstrated that V 10 mg BID increased DNA damage by > 2-fold in 11/22 (50%) on Day 1 and 13/18 (72 %) on Day 4 after 24 hrs of T+C. A PAR ELISA demonstrated that V suppresses PAR levels to <50% of pretreatment values in 21/29 (72%) blood and 9/13 (69%) marrow samples. The MTD has not been reached and dose escalation is ongoing. Disclosures: No relevant conflicts of interest to declare.

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