Probability of Eventual CR After Course 1 of Induction Therapy for Newly-Diagnosed AML As a Function of Platelet and Neutrophil Recovery.

Abstract Abstract 2598 Background: After initial induction chemotherapy for acute myeloid leukemia (AML), it is commonplace that reinduction or intensified therapy is not indicated if the bone marrow has <5% blasts, even despite persistently low neutrophil (ANC) and/or platelet counts. This practice suggests that complete remission (CR), i.e. ANC >1000/μl and platelet count >100,000/μl per standard criteria (Cheson BD, et al. J Clin Oncol. 1990;8(5):813-9), might still occur and that the lack of blood count recovery may not bear prognostic significance. However, the time to CR after the first induction has been shown to be inversely related to subsequent duration of disease-free survival (DFS) and survival (OS), independent of age, treatment, and cytogenetics (Estey EH, et al. Blood. 2000;95(1):72-7). Additionally, the level of ANC and platelet recovery at time of CR is prognostic, with significantly better DFS among patients with higher counts (Yanada M, et al. Leuk Res. 2008;32(10):1505-9). Newly-diagnosed AML patients often present with below normal neutrophil and platelet counts, suggesting that persistence of such cytopenias after induction may be a clinical indicator of minimal residual disease (MRD) in the marrow. We therefore examined whether blood count recovery affected the probability of subsequent CR in patients with <5% bone marrow blasts. Methods: We included 85 patients who, by day 21 or thereafter of induction therapy for newly-diagnosed AML, had not met blood count criteria for CR despite a bone marrow in the prior week with <5% blasts by morphology. Patients were classified by type of induction therapy based on cytarabine dosing. G-CSF was not systematically administered. Marrows were planned for day 21 after chemotherapy and/or weekly thereafter to assess for disease status and evidence of marrow recovery. Because patients were often managed as outpatients, counts and marrows were not uniformly available and thus “day 28” included days 21–28, “day 35” included days 29–35, etc. If a patient had more than one marrow evaluation after day 21, we included only the first one. Results: Overall cohort CR rate was 64%. Eventual CR rate was significantly affected by platelet count, with 44% eventual CR for patients with platelets <30,000, 66% CR for platelets 30,000–100,000, and 95% CR for platelets >100,000. The effect of ANC recovery on eventual CR was less dramatic, with an OR 0.4 (0.2–1.0, p=0.049), for ANC <0.1 vs. >0.1 in the univariate analysis. By day 28, patients with either ANC or platelet recovery were significantly more likely to obtain CR than patients with neither count recovery (89% vs. 51%), OR 8.05 (2.2–30, p=0.002). In the multivariate analysis, (a) lack of platelet recovery to >30,000 was associated with significantly lower incidence of CR, OR 0.26 (0.1–0.8, p=0.02), and was independent of cytogenetic risk, antecedent hematologic disorder, and induction regimen, and (b) there was a suggested association between earlier count recovery and CR (>28 days vs. day 21–28), OR 0.31 (0.1–1.0, p=0.051). Conclusion: Persistence of low peripheral blood counts, despite the presence of <5% bone marrow blasts, is predictive of low eventual CR rates after induction chemotherapy. These results suggest that initiation of further and possibly different therapy, rather than continued observation, should be investigated in this setting. Disclosures: Becker: Sanofi: Research Funding.

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Probability of Eventual CR After Course 1 of Induction Therapy for Newly-Diagnosed AML As a Function of Speed of Neutrophil and Platelet Recovery

Blood ◽

10.1182/blood.v118.21.1498.1498 ◽

2011 ◽

Vol 118 (21) ◽

pp. 1498-1498

Author(s):

Laura F Newell ◽

Ravinder K Sandhu ◽

Pamela S Becker ◽

John M. Pagel ◽

Paul C. Hendrie ◽

...

Keyword(s):

Bone Marrow ◽

Induction Chemotherapy ◽

Induction Therapy ◽

Conflicts Of Interest ◽

Residual Disease ◽

Cell Transplant ◽

Specific Patient ◽

Platelet Recovery ◽

Hematologic Disorder ◽

Count Recovery

Abstract Abstract 1498 Background: After the initial induction chemotherapy for AML, physicians are often reluctant to offer further treatment if the bone marrow has <5% blasts, even in the setting of persistently low neutrophil (ANC) and/or platelet (plt) counts. This reluctance would seem to presume that complete remission (CR) might still occur in these patients without further treatment. However, it has been shown that there is an inverse relation between (A) time to achievement of CR after course 1 of induction therapy and subsequent survival1 and (B) level of ANC and plt count at CR and subsequent relapse-free survival2, with (A) and (B) independent of each other and of cytogenetics and antecedent hematologic disorder. Because patients often present with low ANC and plt counts, these data suggested that their persistence was a clinical indicator of minimal residual disease (MRD) in the marrow, and prompted us to examine whether slow ANC and/or plt recovery despite a marrow with <5% blasts affected the probability of subsequent CR. Methods: We included patients who, at various times after course 1 of induction chemotherapy, had not achieved both ANC >500 and plt >50,000, despite a bone marrow in the prior week with <5% blasts by morphology and flow cytometry. We originally selected these times to be day 28, day 35, day 42, and day 49; however because patients were often treated as outpatients, counts at these specific days were not uniformly available, and thus “day 28” included days 21–28, etc. A variety of “intensive” induction regimens were used. We examined whether incomplete count recovery, defined as (a) neither ANC >500 nor plt >50,000 or (b) either ANC >500 or plt >50,000 but not both, affected eventual CR rates as a function of days from induction chemotherapy. Results: Seventy-five patients were eligible for analysis, including 3 patients with blood and marrow assessments done at 2 time points (ANC <500 and plt <50,000 at days 28/42, 35/42, and 35/42). Median patient age was 53 years (range 18–78), with an antecedent hematologic disorder seen in 28 patients (37%). By SWOG cytogenetic risk categories, 12 patients (16%) had favorable, 35 (47%) intermediate, 21 (28%) unfavorable, and 7 (9%) unknown risk. Eventual course 1 CR rates for the specific patient groups are indicated below, with only the first time point included for each of the above 3 patients with multiple evaluations. At day 28, patients with ANC <500 and plt<50,000 were much less likely to obtain CR than patients with either ANC >500 or plt>50,000 (31% vs. 85%, p=0.001). As time from start of treatment increased without rise in ANC to >500 and plt to >50,000, the probability of subsequent CR decreased (p=0.03) despite a marrow with < 5% blasts by both morphologic and flow assessment. Conclusion: Persistence of ANC <500 and/or plt <50,000, despite the presence of <5% bone marrow blasts, is predictive of low eventual CR rates after induction chemotherapy, with the likelihood of obtaining CR decreasing with greater time from start of induction chemotherapy. We are particularly interested in seeing whether blood count recovery data adds information to such pretreatment predictors of CR as cytogenetics, age, and presence of antecedent hematologic disorder, and in examining the relation between sluggish count recovery and induction regimen, marrow cellularity, and degree of MRD by flow. However, our data suggests that optimism regarding the possibility of CR without further therapy (e.g. hematopoietic cell transplant) should wane in the setting of slow ANC and/or platelet recovery after course 1 of induction chemotherapy. Disclosures: No relevant conflicts of interest to declare.

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Platelet Factor 4 Regulates Platelet Count In Vivo: Implications for Platelet Recovery after Cytotoxic Therapy.

Blood ◽

10.1182/blood.v106.11.3144.3144 ◽

2005 ◽

Vol 106 (11) ◽

pp. 3144-3144

Author(s):

Michele P. Lambert ◽

M. Anna Kowalska ◽

Mortimer Poncz

Keyword(s):

Bone Marrow ◽

Platelet Count ◽

Mononuclear Cells ◽

Physiological Role ◽

Platelet Factor 4 ◽

Cytotoxic Therapy ◽

Platelet Factor ◽

Platelet Recovery ◽

Platelet Counts

Abstract Platelet factor 4 (PF4), a platelet-specific CXC chemokine, was the first reported negative autocrine regulator of megakaryopoiesis in vitro. To define the physiological role(s) of PF4, we established mice that either were deficient in murine (m) PF4 (mPF4−/−) or that over-expressed human (h) PF4 (hPF4+/+). These mice had a level of PF4 ~6-fold greater than that present in human platelet controls. All lines studied had been backcrossed onto a C57Bl/6J background for >10 generations. Platelet counts in these animals correlated inversely with PF4 determined expression, beginning with a low platelet count of 702 ± 57 x 103/μL in the hPF4+/+ mice < hPF4+ < wildtype (WT) < mPF4+/− < mPF4−/− mice in which the platelet count was 1,404 ± 117 x 103/μL. The half-life of the platelets from the hPF4+/+ was identical to that of WT mice. Cultured bone marrow mononuclear cells (BMMNC) in serum-free media showed that each line had identical efficiency in growing megakaryocyte colonies, suggesting that megakaryocyte progenitor cells in these different genetic lines were intrinsically normal. Megakaryocyte colony numbers derived from WT BMMNC were reduced by the addition of recombinant PF4 or supernatant from irradiated bone marrow of hPF4+ mice, but not from mPF4−/− mice, suggesting that megakaryocyte lysis in vivo during cytoreductive therapy may contribute to the subsequent thrombocytopenia by releasing PF4. Additionally, a rabbit polyclonal anti-mPF4 antibody (Ab) was able in culture to significantly reverse this inhibitory effect of PF4 on megakaryopoiesis. Preliminary cytoreductive studies using either 600 cGy or 150 mg/kg of 5-fluorouracil (5-FU) intraperitoneally (IP) were performed. In irradiation studies, mPF4−/− mice began to recover on the same day as WT littermates, but they clearly had higher platelet counts at their nadir, with a drop to only 42 ± 7% of baseline vs. 32 ± 6% in the WT mice (n =12 in each arm, p = 0.06). By Day 13, 9 of 12 mPF4−/− mice had recovered to >75% of baseline, while only 3 of 12 WT mice had recovered (p <0.001). hPF4+ mice (n = 7) were studied after 5-FU treatment. Compared to WT littermates (n = 9), the hPF4+ recovered later (15.6 ± 2.2 vs. 11.2 ± 1.5 days, p < 0.0003), and clearly had significantly greater drop to 30 ± 6% vs. 56 ± 9% of baseline (p < 0.00001). By day 15, all of the WT mice had recovered, but only 43% of hPF4+ mice had returned to >75% of baseline platelet count (p = 0.009). To examine if anti-mPF4 Ab was protective of cytotoxic therapy-induced thrombocytopenia, WT mice were treated with 180 mg/kg of 5-FU and were given either anti-mPF4 Ab (25 mg/kg, IV, x 2) or an equal volume of vehicle. By day 5, the Ab-treated group had a platelet count of 45 ± 6% vs. 32 ± 4% in the untreated (n > 13 per arm, p = 0.015). Platelet counts remained higher in the Ab-treated arm throughout the study. By day 10 after intervention, 9 of 16 mice of the Ab-treated arm had platelet counts over 75% of the baseline, while only 3 of 13 control mice did (p < 0.001). Thus, it appears that PF4 is an important negative autocrine regulator of platelet count in vivo. Excessive release of PF4 following cytotoxic therapy may be a mediator of treatment-related thrombocytopenia. Strategies directed to alleviate the consequence of released PF4 may have clinical benefit in ameliorating this thrombocytopenia.

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Clinical Utility of Morphological Evaluation of Day 14 Bone Marrow Biopsies in Acute Myeloid Leukemia Patients Undergoing Standard Induction Chemotherapy: Time to Change Practice?

Blood ◽

10.1182/blood.v124.21.1004.1004 ◽

2014 ◽

Vol 124 (21) ◽

pp. 1004-1004 ◽

Cited By ~ 1

Author(s):

Yehuda E. Deutsch ◽

German Campuzano-Zuluaga ◽

Matthew P Salzberg ◽

Alexandra Gomez Arteaga ◽

Justin M. Watts ◽

...

Keyword(s):

Bone Marrow ◽

Induction Chemotherapy ◽

Induction Therapy ◽

Predictive Value ◽

Chromosomal Abnormalities ◽

Conflicts Of Interest ◽

Lymphoblastic Leukemia ◽

Response To Treatment ◽

Bone Marrow Biopsies ◽

Count Recovery

Abstract Introduction Early bone marrow (BM) evaluation (during aplasia or at “day 14” (D14)) in patients with AML undergoing conventional induction therapy has been adopted from clinical practice in pediatric acute lymphoblastic leukemia (ALL). While it has been shown that early persistence of AML correlates with decreased complete remission (CR) rates and overall survival (OS), unlike in ALL, there are no data to indicate that early initiation of re-induction therapy based on these findings will positively influence outcome. In fact, early re-induction, especially in older patients, may increase morbidity and mortality from prolonged cytopenias, infectious complications, and longer hospital stays. Moreover, it can be challenging to determine the nature of scattered blasts identified in a hypocellular BM at D14, as they may represent normal recovering marrow elements or malignant blasts. Even if malignant, the chemosensitivityof these cells will only be fully determined by later assessment of the BM at the time of expected count recovery (“day 28”). For these reasons, early re-induction therapy may not be advisable. In this retrospective study, we sought to evaluate the validity of D14 BM assessments as post-therapy prognostication to guide treatment decisions in AML. Methods We conducted a retrospective institutional study (2006-2014) of AML patients undergoing routine induction chemotherapy where diagnostic, interim (around D14) and recovery (D21-42) BM evaluations were available for review. Clinical information and pathology data were retrieved from our institutional database. Responses at D14 were categorized morphologically into three categories: optimal response (OR, blasts ≤5%), indeterminate response (IR, blasts 6-19%), and residual leukemia (RL, blasts ≥20% or a relative decrease in blast count from baseline of <20%). Published response criteria were used to define responses at marrow recovery. Suboptimal response (SOR) at D14 was defined as either IR or RL during the assessment period. Mann-Whitney's U test was used to compare non-normally distributed variables. The Fisher's exact test was employed to assess for associations between response to treatment at D14 and likelihood of recovering in CR. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of a D14 BM to predict CR were calculated for patients that were observed without re-induction. Results Evaluable patients (n=98) had a mean age of 51 years (20-73), and 45% were male. The median BM blast percentages at diagnosis, D14 and recovery were respectively 54.5%, 0% and 2.5% (Figure 1). There was a significantly greater absolute decrease in blast percentage from diagnosis to D14 in patients who recovered in CR compared to those who did not achieve CR (median: 53.5% vs 23.0%, P = 0.001). In patients that got early re-induction therapy for SOR at D14, the relative differential in baseline and D14 BM blasts was significantly lower compared to patients with D14 SOR who did not get re-induction therapy (median: 21.8% vs 77.8%, P=0.004) Ninety patients did not receive early re-induction therapy. Of these, 86 (95.6%) achieved CR and 4 patients (4.4%) recovered counts with residual leukemia. Fourteen (14.3%) patients were classified as SOR at D14. Of these, 6 (6.7%) did not receive re-induction therapy and 4 of these 6 patients (67%) achieved a CR. Eight patients received early re-induction therapy based on SOR at D14 (IR = 2, RL = 6); of these, 4 patients (50%) achieved CR at count recovery. Achieving an OR at D14 was predictive of achieving CR at recovery (sensitivity = 95.3%, PPV = 97.6%). However, not achieving an OR at D14 had low specificity (50%) and NPV (33.3%) for achieving CR (P = 0.021). Conclusions Our results indicate that a SOR at the D14 BM evaluation does not uniformly identify patients with primary induction failure (low NPV) and should not be used to dictate the timing of re-induction therapy. We confirmed the PPV of achieving an OR at D14 as previously reported, but we argue that no additional prognostic data is provided by an OR at D14, beyond what can already be predicted by pre-treatment variables (e.g., age and chromosomal abnormalities). We suggest that the D14 BM should be omitted from the routine evaluation of AML patients during induction therapy outside the context of a clinical trial. Figure 1 Figure 1. Progression and percentage of blasts at diagnosis, day 14 and recovery assessments (n = 98). Disclosures No relevant conflicts of interest to declare.

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Impact of Post-Remission Maintenance Therapy (MT) on Outcomes in Patients (pts) with Newly Diagnosed Acute Myeloid Leukemia (AML) in Real-World Practice

Blood ◽

10.1182/blood-2021-148044 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4140-4140

Author(s):

Ravi Potluri ◽

David Rotter ◽

Zephirin Kiendrebeogo ◽

Clara Chen

Keyword(s):

Bone Marrow ◽

Maintenance Therapy ◽

Induction Chemotherapy ◽

Real World ◽

Cox Regression ◽

The United States ◽

Hazard Ratio ◽

Newly Diagnosed ◽

Ecog Ps ◽

Bone Marrow Blasts

Abstract INTRODUCTION : Therapeutic advances have led to improved survival outcomes in patients (pts) with AML. Consolidation therapy helps to eradicate residual leukemia and prevent relapse. However, relapse remains a major concern and contributes to suboptimal outcomes in pts with newly diagnosed AML who attain remission following induction chemotherapy (IC). Strategies for maintenance therapy (MT) attempt to prolong AML remission and extend survival. MT approaches have included chemotherapy, hypomethylating agents (HMAs), and targeted small-molecule drugs. Overall, the evidence in favor of MT is limited. The oral formulation of azacitidine (Oral-AZA), an HMA, is the first and only MT to demonstrate significant overall survival (OS) and relapse-free survival (RFS) benefits in pts with a broad range of AML subtypes (Wei, NEJM 2020), leading to regulatory approvals in the United States (2020), Canada (2021), and European Union (2021). This study aimed to determine in real-world practice whether the use of MT after IC, with or without consolidation, conferred any clinical advantage before Oral-AZA became available. METHODS: This study included pts in the US-based Flatiron TM Health cancer-specific electronic health record-derived database diagnosed with AML between January 2014 and December 2020. Eligible pts in this study obtained remission (< 5% bone marrow blasts) from first-line (1L) induction chemotherapy or venetoclax (VEN)-based therapy, had not previously taken Oral-AZA or any clinical study drug, and did not undergo transplant prior to relapse. Pts were grouped into 2 cohorts: Cohort A comprised pts who did not receive MT, and Cohort B comprised pts who did receive MT. RFS and OS were estimated using Kaplan-Meier (KM) methods. Multivariate Cox regression models that retained baseline (BL) characteristics (age, sex, BMI, ECOG performance status [PS], and cytogenetic risk) were used to examine the relationships between use of MT and relapse (> 5% bone marrow blasts), and MT and survival. RESULTS: A total of 952 pts met the selection criteria: 808 pts (84.9%) in Cohort A and 144 pts (15.1%) in Cohort B. The most commonly received MTs for pts in Cohort B were injectable AZA (34.7%; n = 50), decitabine (24.3%; n = 35), and VEN-based regimens (21.5%; n = 31). Cohorts A and B were comparable for sex, BL BMI, ECOG PS score, and practice type (Table). Pts who did not receive MT (Cohort A) were younger (mean age 62.1 vs 66.0 years; P = 0.006) and more commonly presented with favorable cytogenetic risk (17.2% vs 6.9%; P = 0.011) compared with pts who received MT (Cohort B). The percentage of pts receiving IC in a 7+3 regimen was similar between Cohort A and Cohort B (69.1% vs 67.4%, respectively; P = 0.685), as were the proportions of pts receiving VEN + an HMA (23.3% vs 17.4% P = 0.118). The KM analysis indicated that although median RFS of Cohort A was longer than Cohort B, differences between cohorts were not statistically significant (303 vs 276 days, P = 0.175). In a subanalysis of pts with intermediate/poor cytogenetic risk, median RFS was 201 days for Cohort A and 230 days for Cohort B (P = 0.952). In the multivariate Cox model, treatment with MT was not a significant predictor of improved RFS vs no MT (hazard ratio [95% CI]: 0.97 [0.79, 1.20]). Age and cytogenetic risk were significantly associated with RFS. The median OS was 659 days for Cohort A and 389 days for Cohort B (P = 0.006). In the subanalysis excluding pts with favorable or unknown cytogenetic risk, median OS was 400 days for Cohort A and 366 days for Cohort B (P = 0.561). A multivariate Cox regression model suggested that treatment with MT was not a significant predictor of improved OS (hazard ratio [95% CI]: 0.88 [0.70, 1.10]). Age, sex, ECOG PS, and cytogenetic risk were all significantly associated with OS. CONCLUSIONS: These Flatiron data provide real-world evidence that despite decades of study, optimal MT in AML had remained elusive. Prior to approval of Oral-AZA, the most common MT options for pts with AML in first remission after 1L induction therapy were limited and appeared to lack clinical benefit. Pts with AML need an MT that prolongs remission and improves long-term survival. Further research is needed to elucidate the benefits and disadvantages of different MT options and may lead to establishment of optimal MT as standard of care. Figure 1 Figure 1. Disclosures Potluri: Bristol Myers Squibb: Consultancy. Rotter: SmartAnalyst Inc.: Current Employment. Chen: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company.

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Platelet Factor 4 Levels Inversely Correlate with Platelet Transfusion Needs In Pediatric Patients Treated for Standard Risk Acute Lymphoblastic Leukemia

Blood ◽

10.1182/blood.v116.21.725.725 ◽

2010 ◽

Vol 116 (21) ◽

pp. 725-725

Author(s):

Michele Lambert ◽

Alisa Reznikov ◽

Yvonne Nguyen ◽

Lubica Rauova ◽

Mortimer Poncz

Keyword(s):

Bone Marrow ◽

Platelet Count ◽

Platelet Transfusion ◽

Pediatric Patients ◽

Human Platelet ◽

Lymphoblastic Leukemia ◽

Platelet Factor ◽

Platelet Counts ◽

Standard Risk ◽

Count Recovery

Abstract Abstract 725 Platelet factor 4 (PF4) is a chemokine found almost exclusively in megakaryocytes and platelets. PF4 has been previously shown to be a negative paracrine inhibiting megakaryopoiesis in vitro in humans and mice. We confirmed this finding and also found an inverse correlation between PF4 and steady-state platelet counts in mice. In both chemotherapy- and radiation-induced thrombocytopenia, platelet PF4 levels inversely correlated with platelet count recovery after bone marrow injury, and blocking this effect ameliorated the thrombocytopenia. We now asked whether platelet PF4 levels are of clinical relevance on human platelet biology in patients undergoing chemotherapy. We selected pediatric patients who had completed treatment for standard risk acute lymphoblastic leukemia at the Children's Hospital of Philadelphia, as this was a fairly large population that have reached remission after relatively uniform therapy. Enrolled patients had completed therapy since January 1999. Blood samples were obtained and medical records were retrospectively reviewed for platelet counts, platelet transfusion requirements and duration of therapy during delayed intensification (DI). DI was chosen for investigation as a preliminary study showed that 35% of our patients require platelet transfusion during DI and need for transfusion at that point in therapy is unlikely to be related to primary underlying bone marrow disease. To date, 68 subjects have been enrolled. Sixty-two subjects had evaluable PF4 levels. PF4 levels were independent of age and sex. Leukemia survivors did not have significantly different PF4 levels when compared to a pediatric control population. There was a direct relationship between measured total PF4 level and platelet count (Pearson r 0.36, p<0.006) although contrary to animal studies, there was no correlation between PF4 per platelet and platelet count. Transfusion data from the first 22 patients have been evaluated. Patients who did not require platelet transfusion during DI had markedly lower PF4 per platelet (6.35 ± 1.85 SE) when compared to patients who required transfusion (13.26 ± 1.89 SE, p<0.02). In addition, duration of therapy (for girls) was inversely correlated with PF4 per platelet (r 0.689, p=0.04), consistent with animal data in which platelet count recovery was inversely correlated with PF4 per platelet. These data suggest that PF4 may be an important in vivo regulator of human platelet counts in the setting of bone marrow injury. Further clinical studies will confirm these findings and begin to explore potential interventions to allow for intensified chemotherapy regimens in subjects at risk for more severe chemotherapy-induced thrombocytopenia based on their level of this negative paracrine of megakaryopoiesis. Disclosures: No relevant conflicts of interest to declare.

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Comparison between Hypercvad and CALLG2008 Protocol in Adult Patients with Newly Diagnosed Acute Lymphoblastic Leukemia:a Single Center Study

Blood ◽

10.1182/blood-2019-129759 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5122-5122

Author(s):

Yang Yingying ◽

He Huang ◽

Yongxian Hu

Keyword(s):

Bone Marrow ◽

Complete Remission ◽

Induction Chemotherapy ◽

Induction Therapy ◽

Neutrophil Count ◽

Molecular Evidence ◽

Routine Practice ◽

Transfusion Rate ◽

Newly Diagnosed ◽

Grade 3

BACKGROUD: HyperCVAD is one of the most frequent used protocols in adult ALL in routine practice. On the other hand, the CALLG2008 protocol was a published protocol designed by the Chinese Acute Lymphoblastic Leukemia Cooperative Group for adult ALL. In this retrospective study, we analyzed 70 Chinese patients with adult ALL to compare the efficacy, safety and costs of HyperCVAD regimen in comparison to CALLG2008. METHODS: Pts ≥ 15 years old with previously untreated newly-diagnosed ALL were eligible. All pts provided IRB-approved informed consent before chemotherapy. HyperCVAD and CALLG2008 were given as initially described. Imatinib (400 mg daily) was administered concurrently in patients with Ph-positive ALL. Prophylactic antibiotics, antifungals, and antiviral agents were provided according to the institutional guidelines. Red blood cells and platelet transfusions were given for hemoglobin<60 g/L and platelets≤10×109/L or if with hemorrhage. Granulocyte colony-stimulating factor was given routinely. Bone marrow aspiration was performed after the completion of the first course of induction chemotherapy to assess their response to treatment. All patients were evaluated for minimal residual disease (MRD) in bone marrow at the end of the first course of induction by 6-color multi-parametric flow cytometry analysis and reverse-transcription quantitative polymerase chain reaction (RT-qPCR). Primary endpoint of the study was CR rate after the first course of induction therapy. Complete remission (CR) was defined as having <5% marrow blasts, a normalization of peripheral counts (neutrophil count ≥1 × 109/L, platelet count ≥100 × 109/L, and no abnormal peripheral blasts), and absence of extramedullary disease. The criteria for the positive and negative MRD are based on the experience of the European ALL MRD Detection Research Collaborative Group. Adverse events occurring during the first 8 weeks after the first course of induction therapy are reported. Other treatment outcomes including blood transfusion requirement, recovery day of neutrophil count were collected, as well as detailed data regarding hospitalization time, complications and costs. RESULTS: Thirty patients were treated with HyperCVAD, and 40 with CALLG2008. Pre-treatment characteristics are shown in the Table 1. After the first course of induction chemotherapy, complete remission was obtained in 83% and 78% of patients, respectively. The CR rate did not vary significantly by different regimens, gender, age, immunophenotype. However, 96% of those with cytogenetic or molecular evidence of the Philadelphia (Ph) chromosome and 76% of those without such evidence achieved a CR (P=0.045). In Ph-negative group, MRD-negative rates were found to be significantly higher with HyperCVAD (58% vs 27%, P=0.036). The median durations of neutrophil recovery of CALLG2008 group was 4 days longer than HyperCVAD group (P=0.038). Moreover, grade 3-4 thrombocytopenic (<500/μl) was more frequent on CALLG2008 regimens compared with the HyperCVAD regimens (90% vs 63%; P=0.007). Accordingly, a lower platelet transfusion rate was observed in favor of the HyperCVAD group (47% vs 73%, P=0.007). The CALLG2008 regimen had more all-grade hepatic toxicity than HyperCVAD regimen (53% vs 27%; P=0.03). Grade 3-4 hypofibrinogenemia was more frequent on CALLG2008 regimen compared with hyper-CVAD regimen (33% vs 7%; P=0.009). The average time to stay of the first course of chemotherapy were 19.4±3.5 and 24.2±8.6 days in HyperCVAD and CALLG2008 groups, respectively (P=0.002). The average drug-related costs for patients treated with HyperCVAD were significantly lower compared with that for those treated with CALLG2008 (30981.7 vs 59422.9 yuan, P=0.010). CONCLUSION: Although HyperCVAD and CALLG2008 regimens showed relatively similar early CR rate, the former yields deep remissions more powerfully in Ph-negative ALL. Additionally, HyperCVAD was more favorable in hematopoietic recovery than CALLG2008. Differences were also observed in terms of less complications, shorter hospitalization and lower drug-related expenditure in favor of HyperCVAD group. Disclosures No relevant conflicts of interest to declare.

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Final Results of the First-in-Human Clinical Study Incorporating Hyperbaric Oxygen into Umbilical Cord Blood Transplantation

Blood ◽

10.1182/blood.v126.23.1909.1909 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1909-1909

Author(s):

Omar S. Aljitawi ◽

Siddhartha Ganguly ◽

Tara L. Lin ◽

Shana Palla ◽

Chris Lominska ◽

...

Keyword(s):

Platelet Count ◽

Median Time ◽

Umbilical Cord Blood ◽

Blood Count ◽

Hematologic Malignancies ◽

P Value ◽

Survival Curves ◽

Platelet Recovery ◽

Neutrophil Recovery ◽

Count Recovery

Abstract Background: Umbilical cord blood (UCB) transplantation is associated with delayed blood count recovery and engraftment. We have demonstrated that pre-treatment with hyperbaric oxygen (HBO) therapy to the recipient mice improved engraftment of intravenously infused human UCB CD34+ in a murine transplant model. Further studies from our laboratory attribute HBO effects on engraftment to HBO-induced low erythropoietin (EPO) state in the host, resulting in early UCB CD34+ cell bone marrow homing and an increase in myeloid to erythroid differentiation. These results lead to the first in-human pilot clinical trial investigating the safety of HBO in the setting of UCB transplantation and secondarily evaluating time to blood count recovery. Herein, we report the final results of this study in comparison to our historic institutional data to determine the impact of HBO on blood count recovery and day +100 survival. Materials/methods: Enrolled patients had hematologic malignancies that required reduced intensity conditioning (RIC) or myeloablative conditioning (MAC) and UCB transplantation. They received HBO therapy on day 0 consisting of exposure to 2.5 atmosphere absolutes for a total of 2 hours, in a single hyperbaric chamber, breathing 100% oxygen. Six hours from the start of HBO, single or double UCB units were intravenously infused and patients were followed daily for toxicity and blood count recovery. Serum EPO levels were measured by enzyme-linked immunosorbent assay (ELISA). Mycophenolate mofetil and cyclosporine were used for GVHD prophylaxis. Charts of 48 patients who received UCB transplantation at our institution for hematologic malignancies between 2008 and 2013 were reviewed for comparison. Results: 15 patients, 9 males (60%) and 6 females (40%), with a median age of 44 years (17-70) were treated. One patient had lymphoma and 14 patients had acute leukemia; 10 in first remission and 4 in second remission. Eight patients received one UCB unit and 7 received two units. Patients received a median total nucleated cell dose of 3.02(1.67-4.51) ×107/Kg recipient body weight (BWT), a median CD34 cell dose of 1.2 (0.7-6.5) ×105/Kg recipient BWT, and 9/15 patients received RIC. 14/15 treated patients completed the planned therapy, while one patient did not finish the last 15 minutes due to nausea. None of the patients experienced an unexpected toxicity. All patients engrafted except for one patient who demonstrated prompt autologous blood count recovery. Full donor chimerism was achieved in 7/8 (88%) of engrafted RIC patients 30 days post-transplant. Eleven of the 15 (67%) patients developed acute graft versus host disease at time of engraftment; 36% developed grade I, 54% had grade II and 9% had grade III. On average, EPO levels 8-hours post HBO were 56 (27-92) % of their pre-HBO values. Median time to neutrophil count recovery, median time to platelet count recovery, day +100 survival (Figure-1), percentage of patients who achieved neutrophil recovery and platelet count recovery in the HBO and historic cohorts are summarized in table-1. Conclusions: HBO therapy prior to UCB cell infusion appears to be safe and well-tolerated in the setting of clinical UCB transplantation. Given the potential benefits of relatively fast recovery and lack of toxicity, HBO should be further evaluated as a strategy to promote engraftment in UCB transplantation. Table 1. Summary of transplant outcomes in HBO and historic cohorts. All MAC RIC HBO (n=15) Historic (n=48) P value HBO (n=6) Historic (n=21) P value HBO (n=9) Historic (n=27) P value Day 100 survival (n/%) No - (0%) 11 (24%) 0.051 - (0%) 10 (48%) 0.03 - (0%) 1 (4%) NS Yes 15 (100%) 34 (76%) 6 (100%) 11 (52%) 9 (100%) 23 (96%) Neutrophil recovery (n/%) No - (0%) 6 (12%) NS - (0%) 4 (19%) NS - (0%) 2 (7%) NS Yes 15 (100%) 42 (88%) 6 (100%) 17 (81%) 9 (100%) 25 (93%) Platelet recovery (n/%) No - (0%) 15 (31%) 0.013 - (0%) 11 (52%) 0.023 - (0%) 4 (15%) NS Yes 15 (100%) 33 (69%) 6 (100%) 10 (48%) 9 (100%) 23 (85%) Median time to neutrophil recovery (Range) 14 (6-45) 20.5 (5-71) NS 24.5 (16-45) 33 (13-71) NS 7 (6-17) 14 (5-28) NS Median time to platelet recovery (Range) 37.5 (0-85) 38 (0-161) NS 54.5 (30-84) 50 (29-161) NS 32 (0-85) 38 (0-112) NS Figure 1. Day+100 survival curves. Figure 1. Day+100 survival curves. Disclosures No relevant conflicts of interest to declare.

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Necrotizing Hemorrhagic Gastritis following Acute Myeloid Leukemia Induction with Midostaurin: An Unexpected Complication

Acta Haematologica ◽

10.1159/000500975 ◽

2019 ◽

Vol 143 (1) ◽

pp. 65-68 ◽

Cited By ~ 3

Author(s):

Shai Shimony ◽

Hilla Reiss Mintz ◽

Yulia Shvartser Beryozkin ◽

Avivit Shoham ◽

Pia Raanani ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Blood Count ◽

Chemotherapy Regimen ◽

Rare Complication ◽

Intensive Chemotherapy ◽

Newly Diagnosed ◽

Multikinase Inhibitor ◽

Acute Myeloid ◽

Count Recovery

Midostaurin is a tyrosine multikinase inhibitor approved for the treatment of patients with newly diagnosed acute myeloid leukemia (AML) with mutated Fms-like tyrosine kinase-3. We describe a case report of a 49-year-old AML patient treated with an intensive chemotherapy regimen followed by midostaurin. After achieving complete remission with blood count recovery, he suffered from a serious, rare complication of necrotizing hemorrhagic gastritis with no evidence of infection or malignant infiltration, possibly associated with midostaurin therapy.

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Platelet Decrease and Efficacy of Platelet-Rich Plasma Return for Peripheral Blood Stem Cell Apheresis

Blood ◽

10.1182/blood-2020-142316 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 29-30

Author(s):

Takahiro Shima ◽

Teppei Sakoda ◽

Tomoko Henzan ◽

Yuya Kunisaki ◽

Takahiro Maeda ◽

...

Keyword(s):

Multivariate Analysis ◽

Stem Cell ◽

Platelet Count ◽

Peripheral Blood ◽

Peripheral Blood Stem Cell ◽

Platelet Rich Plasma ◽

Blood Stem Cell ◽

Platelet Recovery ◽

Platelet Counts ◽

Cd34 Cells

Peripheral blood stem cell (PBSC) transplantation is a key treatment option for hematological diseases and widely performed in clinical practice. Platelet loss is the major complication of PBSC apheresis, and platelet-rich plasma (PRP) return is recommended in case of severe platelet decrease following apheresis; however, little is known about the frequency and severity of platelet loss nor the efficacy of PRP return post-apheresis. To address these questions, we assessed changes in platelet counts following PBSC-related apheresis in 270 allogeneic (allo)- and 105 autologous (auto)-PBSC settings. We also evaluated efficacy of PRP transfusion on platelet recovery post-apheresis. Platelet counts reduced up to 70% post-apheresis in both allo- and auto-PBSC settings, while severe platelet count decrease (< 50 x 109/L) was only observed in auto-PBSC patients (Figure 1). We next analyzed the relationship between severe platelet (< 50 x 109/L) after apheresis and several clinical factors by using univariate and multivariate analysis for auto-PBSC patients. As shown in Table 1, in univariate analysis, severe platelet counts following auto-PBSC apheresis was found more frequently in patients with lower platelet count, lower percentage of CD34+ cells in PB at pre-apheresis, repeated round of apheresis, and smaller number of collected CD34+ cells. On the other hand, in multivariate analysis, the white blood cell (WBC) counts pre-apheresis was the only significant risk factor of severe platelet count following apheresis (p = 0.038). We finally analyzed the transitions of platelet counts in the setting of apheresis. The median platelet counts at pre-apheresis, post-apheresis, and post-PRP return were 187.0 x 109/L, 132.0 x 109/L, and 154.0 x 109/L for allo-PBSC apheresis, and 147.0 x 109/L, 111.0 x 109/L, and 127.0 x 109/L for auto-PBSC apheresis (p < 0.0001 for all, allo-PBSC donors and auto-PBSC patients, respectively) (Figure 2), indicating that PRP return post-apheresis facilitated a rapid platelet recovery in both allo- and auto-settings. Collectively, our data suggest that WBC counts pre-apheresis is a useful predictor for severe platelet decrease following auto-PBSC apheresis and that PRP return is an effective mean to facilitate platelet recovery post-apheresis. Disclosures No relevant conflicts of interest to declare.

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Nutritional Status of the Children with Acute Lymphoblastic Leukemia at Diagnosis and after Completion of Induction

Haematology Journal of Bangladesh ◽

10.37545/haematoljbd202174 ◽

2021 ◽

Vol 5 (02) ◽

pp. 50-56

Author(s):

Noor-A-Sabah Liza ◽

S. M. Rezanur Rahman ◽

Afiqul Islam ◽

Chowdhury Yakub Jamal ◽

Mohosina Sultana Setu ◽

...

Keyword(s):

Nutritional Status ◽

Serum Albumin ◽

Induction Chemotherapy ◽

Induction Therapy ◽

Serum Albumin Level ◽

Albumin Level ◽

Anthropometric Measurements ◽

Newly Diagnosed ◽

Significant Difference ◽

Nutritional Status Of Children

Background: Adequate nutrition is an important concern in children with leukemia. Malnutrition and weight lost are common and are due to verity of mechanism involving the tumor, the host response to the tumor such as infection and pharmacokinetics of chemotherapeutic drugs. Objective: To evaluate and compare the nutritional status of children with ALL at diagnosis and after completion of induction therapy. Methodology: This prospective observational study included 60 children newly diagnosed as ALL, aged 2-15 years, over a period from April 2012 to September 2012 in the Department of Pediatric Hematology and Oncology, BSMMU. The anthropometric measurements and serum albumin level were taken. Anthropometric indices are calculated by NCHS (WHO-2000) and classified as Z score. Children <-2 SD are considered as underweight (WFA), stunted (HFA) and wasted (WFH). Serum albumin level below 21g/dl is considered as severely malnourished. The Hb values of the children are compared with normal values by age. The children got induction chemotherapy according to MRC-11 protocol. They were in regular follow up and again anthropometric measurements and serum albumin level were taken after completion of induction. Results: Out of 60 children with ALL, 48 (70%) were underweight, 45 (75%) were stunted 36 (60%) were wasted at diagnosis. Incidence of malnutrition among leukemia children after completion of induction were 24 (40%) underweight, 45 (75%) were stunted and 6 (10%) were wasted. The results showed that children in the newly diagnosed stage had a higher prevalence of malnutrition. However no statistically significant difference in the nutritional status was found among newly diagnosed and after completion of induction in term of underweight and stunting but newly diagnosed patients had statistically significant wasting than patients who had completed induction chemotherapy. No patient showed severe malnutrition based on the cut-off point for serum albumin on both stages. All the children (100%) had less than normal range hemoglobin levels. Conclusion: Malnutrition was higher in children with newly diagnosed leukemia. Children had significant differences in the nutritional status in term of wasting at diagnosis than after completion of induction therapy. So, the nutritional status of children with leukemia should be monitor periodically.

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