Sequential Conditioning With FLAMSA Does Not Improve Outcomes of Allogeneic Stem Cell Transplantation in Chronic Myelomonocytic Leukemia Patients.

As with myelodysplastic syndromes (MDS), effective treatment options for chronic myelomonocytic leukemia (CMML) are limited, and the optimal treatment approach remains undefined. Allogeneic stem cell transplantation (allo-SCT) is potentially curative therapy for patients with CMML. Sequential conditioning with FLAMSA was initially developed for refractory acute myeloid leukemia and has since been applied in the treatment of MDS and CMML. Data on optimal allo-SCT conditioning in CMML Patients is scarce. This retrospective study from the Department of Stem Cell Transplantation at the University Medical Center Hamburg, Germany, compared allo-SCT outcomes in CMML patients across three conditioning regimes: Thiotepa-busulfan (TB), sequential FLAMSA-busulfan fludarabine (FLAMSA-FB), and treosulfan-fludarabine (Treo-Flu). Sixty-nine consecutive patients with CMML who underwent allo-SCT between the years 2006 and 2022 were included in the study. Twenty-two received TB, 27 received FLAMSA-FB, and 20 received Treo-Flu conditioning. Transplant sources included matched related donors (8 patients), mismatched related donors (8 all in the TB group), matched unrelated donors (31), and mismatched unrelated donors (22) with significant group variations (P < .001). Most patients received anti-T lymphocyte Globulin for graft versus host disease (GVHD) prophylaxis (TB 68%, FLAMSA-FB 93%, Treo-Flu 85%, P = .08). CPSS-Molecular score was comparable between the groups. One TB patient experienced primary graft failure, but engraftment times were comparable across the groups. Although not statistically significant, the TB group showed a trend toward improved 3-year overall survival (OS) rates (80%) compared to FLAMSA-FB (37%) and Treo-Flu (55%) (P = .05). The TB group also displayed significantly higher 3-year progression-free survival (PFS) rates (80%) compared to FLAMSA-FB (33%) and Treo-Flu (both 39%), (P = .02). No significant differences were observed in 3-year non-relapse mortality across the TB (20%), FLAMSA-FB (30%), and Treo-Flu (26%) groups (P = .8). Interestingly, no TB patients relapsed at 3 years, contrasting with the FLAMSA-FB (41%) and Treo-Flu groups (30%, P = .02). Lastly, cumulative incidences of acute and chronic GVHD were similar across groups. Our analysis suggests FLAMSA-FB does not improve transplant outcomes, however, TB represents the preferred conditioning regimen for CMML patients undergoing allo-SCT. It demonstrates notable advantages in relapse prevention and leads to improved OS and PFS compared to FLAMSA-FB and Treo-Flu protocols.

Comparable Results Between 8 and 12 Gray TBI in Combination With Fludarabine and Post-Transplant Cyclophosphamide in MRD-Negative but Not in MRD-Positive Acute Lymphoblastic Leukemia Patients Transplanted in First Complete Remission.

BACKGROUND: The optimal TBI dose for ALL patients undergoing allogeneic SCT is still not clearly defined. METHODS: Single-center retrospective analysis of high-risk ALL patients in CR1 treated with 8 Gy (n = 22) or 12 Gy (n = 50) TBI in combination with fludarabine and PTCy. Median patient age in the 8 Gy TBI cohort was 63 (37-79) and 37 (18-56) in the 12 Gy TBI cohort and median follow-up time was 21 months (range 1-92). RESULTS: OS and LFS at 2 years after 8 Gy were 65% and 55% versus 74% and 74% after 12 Gy (p = 0.3 and p = 0.2, respectively). CIR and NRM at 2 years were 27% and 14% after 8 Gy versus 4% and 20% after 12 Gy (p = 0.004 and p = 0.4, respectively). MRD-positive (+) patients (n = 26) receiving 12 Gy (n = 19) showed better OS (p = 0.01), LFS (p = 0.009), GRFS, lower CIR (p = 0.02), and similar NRM than did MRD+ patients receiving 8 Gy (n = 7). MRD-negative (-) patients (n = 38) receiving 12 Gy (n = 27) had similar OS, LFS, GRFS, lower CIR, and higher NRM (p = 0.04) than did MRD- patients receiving 8 Gy (n = 11). CONCLUSION: Our study demonstrates that 8 Gy TBI in comparison to 12 Gy TBI results in low NRM but a high relapse rate with similar OS, LFS, and GRFS. In MRD+ high-risk ALL patients, allogeneic SCT with 12 Gy TBI leads to improved OS, LFS, GRFS, and a low relapse rate. Prospective studies comparing the different treatment regimens with larger MRD patient cohorts are needed to confirm this data.

Anti-T-lymphocyte globulin (ATLG) compared to post-transplant cyclophosphamide as GvHD prophylaxis in ALL patients undergoing allogeneic stem cell transplantation.

We retrospectively analyzed high-risk ALL patients in CR1 receiving total body irradiation based conditioning regimen with ATLG (n = 74) or PTCy (n = 73) for GVHD prophylaxis. The 3-year OS and LFS were similar in both groups: 65 and 60% in the ATLG group and 64 and 67% in the PTCy group (p = 0.9 and 0.5, respectively). CIR and NRM rate at three years was 12 and 21% after PTCy and 19 and 20% after ATLG (p = 0.4 and p = 0.9, respectively). Acute GvHD grades II-IV and grades III/IV at 100 days was 46 and 19% after PTCy and 33 and 10% after ATLG (p = 0.08 and p = 0.9, respectively). Chronic GvHD of all grade at two years was higher after PTCy: 55% versus 26% (p < 0.001). Based on the propensity score matching (PSM) analysis, aGvHD grades II-IV was trending higher in the PTCy group compared to the ATLG group (p = 0.07). In contrast to the PSM analysis, on multivariate analysis the receipt of PTCy compared with ATLG was associated with a reduced CIR (p = 0.026). Our retrospective single-center analysis shows a lower incidence of acute and chronic GvHD while displaying similar LFS and OS after ATLG compared to PTCy in TBI based allogeneic stem cell transplantation for high-risk ALL.

Reduced intensity versus myeloablative conditioning for MDS: long-term results of an EBMT phase III study (RICMAC).

Short-term outcome of myeloablative (MAC) and reduced intensity (RIC) conditioning in the prospective randomized international EBMT RICMAC study in patients with myelodyplastic syndrome (MDS) was comparable but longer follow up is lacking. Patients with MDS aged 18-65 years were randomized to receive MAC (N = 64) with busulfan/cyclophosphamide or RIC (n = 65) with busulfan/fludarabine followed by stem cell transplantation -(HCT) from HLA matched or mismatched donor. After a median follow-up of 6.2 (0.4-12.5) years, 10-year OS and RFS were 54.0% and 43.9% for RIC and 44.4% and 44.2% for MAC (p = 0.15 and p = 0.78), respectively. Since the first report, 6 patients died on NRM, 4 after RIC, and 2 after MAC. Similarly, 8 patients relapsed (4 in each arm), increasing the number of relapsed patients to 28. The second HCT was performed in 18 pts, 8 in the MAC, and 10 in the RIC arm. In a multivariate analysis, ECOG status and chemotherapy prior to HCT were independent risk factors for OS and RFS, ECOG and low cytogenetic risk for NRM and chemotherapy prior to HCT for RI. Patients with low cytogenetic risk had better OS [p = 0.002], RFS [p = 0.02], and NRM (p = 0.015) after RIC as compared to MAC.

Hematopoietic cell transplantation (HCT) in MDS patients of older age.

Hematopoietic cell transplantation (HCT) has evolved to an essential treatment in younger and more recently in elderly patients with myelodysplastic syndrome (MDS), the age group with the highest incidence. Less intense conditioning regimens and improvements in supportive therapy have reduced considerably transplant related mortality and in the same time increased the access to this curative treatment. Timing of HCT in the course of the disease assumes a crucial role. Detection of disease progression, geriatric assessment, comorbidity evaluation, and identification of transplant-specific risks are becoming increasingly important in this context. Novel statistical methods, molecular biomarkers, and quantification of tumor burden pre- and post-HCT will play an essential role in years to come. More effective and less toxic treatments to reduce the tumor burden before and/or after HCT are expected to improve the outcome. In this review article we discuss the current views and what we can expect.

Graft-versus-host disease and impact on relapse in myelofibrosis undergoing hematopoietic stem cell transplantation.

Allogeneic hematopoietic stem cell transplantation (alloHSCT) remains the only curative treatment for myelofibrosis (MF). Relapse occurs in 10-30% and remains a major factor for dismal outcomes. Previous work suggested that graft-versus-host disease (GVHD) might be associated with risk of relapse. This study included 341 patients undergoing their first (n = 308) or second (n = 33) alloHSCT. Anti-T-lymphocyte or antithymocyte globulin was used for GVHD prophylaxis in almost all patients. Median time to neutrophile and platelet engraftment was 13 days and 19 days, respectively. The cumulative incidence of acute GVHD grade II-IV was 41% (median, 31 days; range, 7-112). Grade III-IV acute GVHD was observed in 22%. The cumulative incidence of chronic GVHD was 61%. Liver was affected in 23% of acute GVHD cases and 46% of chronic GVHD cases. Severe acute GVHD was associated with high non-relapse mortality. The development of acute GVHD grade II and moderate GVHD was an independent factor for reduced risk for relapse after transplantation without increased risk for non-relapse mortality, while especially acute GVHD grade IV was associated with high non-relapse mortality. Last, we identified that ongoing response to ruxolitinib, accelerated-phase MF at time of transplantation and splenectomy prior to transplantation were independent predictors for relapse.

Transplantation in CML in the TKI era: who, when, and how?

Molecular therapy with tyrosine kinase inhibitors (TKIs) has significantly reduced the indication for allogeneic hematopoietic stem cell transplantation (allo-HSCT) in chronic myeloid leukemia (CML). Treatment-free remission can be obtained in about 50% of patients with an optimal response. However, cure rates up to 90% are restricted to patients receiving HSCT. Timing is essential since HSCT in the early stages of the disease has the best outcome. Patients in a more advanced phase (AdP) than chronic-phase (chP) CML undergo HSCT with suboptimal outcomes, and the gap between chP and AdP disease is widening. First-line therapy should start with first- or second-generation (G) TKIs. Patients failing treatment (BCR-ABL1 transcripts of greater than 10% at 3 and 6 months and greater than 1% at 12 months) should be switched to second-line TKIs, and HSCT should be considered. Patients not responding to 2G-TKI therapy as well as patients in an accelerated phase (AP) or blast crisis (BC) are candidates for HSCT. Therapy resistant BCR-ABL1 mutations, high-risk additional cytogenetic abnormalities, and molecular signs of leukemia progression should trigger the indication for HSCT. Patients who, despite dose adjustments, do not tolerate or develop severe adverse events, including vascular events, to multiple TKIs are also candidates for HSCT. In AdP CML, TKIs do not show long-lasting results, and the outcome of HSCT is less optimal without pretransplant therapy. In these patients the induction of chP2 with TKIs, either alone (AP) or in combination with intensive chemotherapy (BC), followed by HSCT should be pursued.

Antibody response after vaccination against SARS-CoV-2 in adults with hematological malignancies: a systematic review and meta-analysis.

Vaccines against SARS-CoV-2 have shown remarkable efficacy and thus constitute an important preventive option against coronavirus disease 2019 (COVID-19), especially in fragile patients. We aimed to systematically analyze the outcomes of patients with hematological malignancies who received vaccination and to identify specific groups with differences in outcomes. The primary end point was antibody response after full vaccination (2 doses of mRNA or one dose of vectorbased vaccines). We identified 49 studies comprising 11,086 individuals. Overall risk of bias was low. The pooled response for hematological malignancies was 64% (95% confidence interval [CI]: 59-69; I²=93%) versus 96% (95% CI: 92-97; I²=44%) for solid cancer and 98% (95% CI: 96-99; I²=55%) for healthy controls (P<0.001). Outcome was different across hematological malignancies (P<0.001). The pooled response was 50% (95% CI: 43-57; I²=84%) for chronic lymphocytic leukemia, 76% (95% CI: 67-83; I²=92%) for multiple myeloma, 83% (95% CI: 69-91; I²=85%) for myeloproliferative neoplasms, 91% (95% CI: 82-96; I²=12%) for Hodgkin lymphoma, and 58% (95% CI: 44-70; I²=84%) for aggressive and 61% (95% CI: 48-72; I²=85%) for indolent non-Hodgkin lymphoma. The pooled response for allogeneic and autologous hematopoietic cell transplantation was 82% and 83%, respectively. Being in remission and prior COVID-19 showed significantly higher responses. Low pooled response was identified for active treatment (35%), anti-CD20 therapy ≤1 year (15%), Bruton kinase inhibition (23%), venetoclax (26%), ruxolitinib (42%), and chimeric antigen receptor T-cell therapy (42%). Studies on timing, value of boosters, and long-term efficacy are needed. This study is registered with PROSPERO (clinicaltrials gov. Identifier: CRD42021279051).

COVID-19 and seasonal influenza: a comparative analysis in patients with hematological malignancies.

The severity and mortality of COVID-19 and seasonal influenza were recently compared in the general population but not in patients with hematological malignancies. We analyzed the clinical courses of 79 patients with hematological malignancies and diagnosis of either SARS-CoV-2 (n = 29) or influenza A or B infections (n = 50) who were admitted or were already under treatment in the Department of Oncology, Hematology and Stem cell Transplantation at the University Medical Center Hamburg-Eppendorf, Germany, between 1 January 2012 and 31 January 2021. For COVID-19, we observed significantly higher rates of acute respiratory distress syndrome with 48% (14/29) compared to 14% (7/50) in the influenza group (p = 0.001) as well as a significantly higher virus-associated 90-day mortality (41% vs. 12%, p = 0.005). Based on our results, we conclude that infections with SARS-CoV-2 are more severe than influenza A or B in patients with hematological malignancies.

Current status of pretransplant intensive chemotherapy or hypomethylating agents for myelodysplastic syndrome.

Myelodysplastic syndrome is a heterogeneous disease with survival probabilities ranging from a few months to several years. Allogeneic hematopoietic cell transplantation (HCT) remains the only curative treatment. Although access (up to 75 years) and outcome of HCT have improved steadily in recent years, high relapse rates and, to a lower extent, treatment related mortalities are a persisting problem. Reduction of tumor burden before HCT has been shown to decrease relapse incidence and often overall survival (OS) in hematological malignancies but the role of pretransplant therapy in MDS remains controversial. We reviewed the role of pretransplant therapy on outcome in MDS patients. No prospective randomized trial addressed this issue so far. Retrospective studies have shown that pretransplant therapy reduces the risk of relapse, but does not improve survival. In addition, registry studies from diagnosis with standard protocols are proposed in order to exclude patient selection. With the availability of new, more effective and low-toxicity therapies, it may be possible to achieve a significant improvement of OS in the future.

Risk factors for outcome after allogeneic stem cell transplantation in patients with advanced phase CML.

Allogeneic hematopoietic stem-cell transplantation (HSCT) remains the only curative option for patients with advanced chronic myeloid leukemia (CML). However, outcome is dismal and of short follow-up. The objective of the study was to determine long-term outcome and risk factors in patients with a history of CML Blast Crisis (BC; n = 96) or accelerated phase (n = 51) transplanted between 1990 and 2018. At transplant, patients had a median age of 39 (range 7-76) years and were in ≥CP2 (n = 70), in AP (n = 40) or in BC (n = 37) with a diagnosis-HSCT interval of median 1.9 (range 0.3-24.4) years. Overall survival (OS) amounted 34% (95% CI 22-46) and progression-free survival (PFS) 26% (95% CI 16-36) at 15 years. Adverse risk factors for OS and PFS were low CD34+ count in the graft, donor age (>36 years) and BC. Cumulative incidence of Non-Relapse Mortality (NRM) was 28% (95% CI 18-38) and of relapse (RI) 43% (95% CI 33-53) at 15 years. PB-HSCT and HSCT after 2008 were favorable prognostic factors for NRM, while family donor and patient age >39 years were independently associated with higher RI. HSCT resulted in long-term OS in patients with advanced CML. OS was improved in non-BC patients, with donors ≤36 years and with higher CD34+ dose in the graft.

Hotspot DNMT3A mutations in clonal hematopoiesis and acute myeloid leukemia sensitize cells to azacytidine via viral mimicry response.

Somatic mutations in DNA methyltransferase 3A (DNMT3A) are among the most frequent alterations in clonal hematopoiesis (CH) and acute myeloid leukemia (AML), with a hotspot in exon 23 at arginine 882 (DNMT3AR882). Here, we demonstrate that DNMT3AR882H-dependent CH and AML cells are specifically susceptible to the hypomethylating agent azacytidine (AZA). Addition of AZA to chemotherapy prolonged AML survival solely in individuals with DNMT3AR882 mutations, suggesting its potential as a predictive marker for AZA response. AML and CH mouse models confirmed AZA susceptibility specifically in DNMT3AR882H-expressing cells. Hematopoietic stem cells (HSCs) and progenitor cells expressing DNMT3AR882H exhibited cell autonomous viral mimicry response as a result of focal DNA hypomethylation at retrotransposon sequences. Administration of AZA boosted hypomethylation of retrotransposons specifically in DNMT3AR882H-expressing cells and maintained elevated levels of canonical interferon-stimulated genes (ISGs), thus leading to suppressed protein translation and increased apoptosis.

No advantage of Imatinib in combination with hydroxyurea over Imatinib monotherapy: a study of the East German Study Group (OSHO) and the German CML study group.

INTRODUCTION: The combination of Imatinib (IM) and hydroxyurea (HU) was explored for the treatment of chronic myelogenous leukemia (CML). METHOD: After in vitro testing and a phase I study (n = 20), 59 patients were randomized in the IM/HU and 29 in the IM arm. According to protocol, 49 propensity-score matched IM patients were included from the CML-IV study. RESULTS: Additive specific inhibition of CML cells by IM/HU was detected in vitro. HU 500 mg qd in combination with IM 400 mg qd proved feasible in the phase I study. Overall, no significant difference with respect to major molecular response (MMR) at 18 months (IM/HU and IM 66%; primary endpoint) was observed. Significant differences were noted for MMR at 6 months (p = 0.04) and for cumulative incidences of adverse events (p = 0.03) in favor of IM monotherapy (secondary endpoints). CONCLUSION: IM/HU combination was more potent in selectively inhibiting CML cells in vitro, but not superior to IM in vivo. (NCT02480608).

Two decades of experience in a combined adult/pediatric allogeneic hematopoietic stem cell transplantation center in Algiers, Algeria.

Hematopoietic stem cell transplantation (HSCT) has evolved from an experimental to a successful treatment modality reaching worldwide 80.000 HSCT/year. Distribution and trends of HSCT, however, remain heterogeneous. Activities range from none to more than 511/10 million population between countries and regions. Here, we report on a successful autologous and allogeneic HSCT program for adult and pediatric patients started two decades ago in Northern Africa. From 1998 to December 2017, a total of 2828 HSCT was performed of which 2059 were allo-HSCT (1474 adults and 585 children). The activities were analyzed according to indication, donor type, stem cell source, and trends over time. There was a significant difference in indications according to age. Adult patients were transplanted more often for hematological malignancies. In children, the indications were distributed equally between malignant and non-malignant diseases. Overall activities increased substantially in AML and to a lower extent in ALL and CLL despite sharp reduction of activity in CML after 2005. Finally, a higher transplantation rate (33/10 million population) was reached as compared to most regions of the world except Europe and USA/Canada. Overall survival in children with AML was 56.0% at 15 years, in adults 61.3% at 5 years, and in patients with CML 55.5% at 15 years without difference between reduced intensity condition (RIC) and myeloablative conditioning (MAC). Patients with Ph+ ALL had the lowest survival reaching 26.7% at 5 years. Highest survival was observed in patients with aplastic anemia, Fanconi anemia, and thalassemia reaching 77.3%, 73.5%, and 75.7% at 15 years respectively. Long distances and late referral remain a challenge for this large country.

Chromosome abnormalities at onset of complete remission are associated with worse outcome in patients with acute myeloid leukemia and an abnormal karyotype at diagnosis: CALGB 8461 (Alliance).

Achievement of complete remission is essential for long-term survival of acute myeloid leukemia patients. We evaluated the prognostic significance of cytogenetics at complete remission in 258 adults with de novo acute myeloid leukemia and abnormal pre-treatment karyotypes, treated on Cancer and Leukemia Group B front-line studies, with cytogenetic data at onset of morphological complete remission. Thirty-two patients had abnormal karyotypes at time of initial complete remission. Of these, 28 had at least 1 abnormality identified pre-treatment, and 4 acute myeloid leukemia-related abnormalities not detected pre-treatment. Two hundred and twenty-six patients had normal remission karyotypes. Patients with abnormal remission karyotypes were older (P<0.001), had lower pre-treatment white blood counts (P=0.002) and blood blast percentages (P=0.004), were less often classified as Favorable and more often as Adverse among European LeukemiaNet Genetic Groups (P<0.001), and had shorter disease-free survival (median 0.6 vs. 0.9 years; P<0.001) and overall survival (median 1.2 vs. 2.2 years; P<0.001) than patients with normal remission karyotypes. Sixteen patients with normal remission karyotypes also harbored non-clonal abnormalities unrelated to pre-treatment karyotypes. They had shorter overall survival than 210 patients with only normal metaphases (P=0.04). Forty-eight patients with any clonal or non-clonal chromosome abnormality at complete remission had worse disease-free survival (median 0.6 vs. 1.0 years; P<0.001) and overall survival (median 1.2 vs. 2.5 years; P<0.001) than 210 patients with exclusively normal metaphases. In multivariable analyses, after adjustment for age, the presence of any remission abnormality was associated with shorter disease-free survival (P=0.03) and overall survival (P=0.01). We conclude that detection of any abnormality at complete remission is an adverse prognostic factor. (clinicaltrials.gov identifier: 00048958).