Monitoring Humoral Response Following BNT162b2 mRNA Vaccination against SARS-CoV-2 in Hematopoietic Stem-Cell Transplantation Patients: A Single-Center Prospective Study along with a Brief Review of Current Literature.

Data on antibody response (AR) after vaccination against SARS-CoV2 in hematopoietic stem-cell transplantation setting (HSCT) were initially scarce, mainly due to the exclusion of such patients from approval studies. Shortly after the worldwide application of vaccination against SARS-CoV-2 in vulnerable populations such as patients with hematologic malignancies, limited single-center trials, including HSCT patients, were published. However, there was a great heterogeneity between them regarding the type of underlying malignancy, co-current treatment, type of vaccine, method of AR measurement, and time point of AR measurement. Herein, we present the results of a prospective study on AR after vaccination for SARS-CoV-2 using the BNT162b2 vaccine in a cohort of 54 HSCT recipients-mostly autologous from a single Unit-along with a broad review of the current literature. In our cohort, the AR positivity rate at 1 month was 80.8% and remained positive in 85.7% of patients at 3 months after vaccination. There were only nine non-responders, who were more heavily pretreated and more frequently hypogammaglobulinemic compared to responders. High antibody titers (AT), [AT ≥ 1000 U/mL], were detected in 38.5% and 30.6% of the patients at m1 and m3, respectively. A significant decline in AT between m1 and m3 was demonstrated-p < 0.0001; median AT1 and AT3 were 480.5 and 293 U/mL, respectively. A novel finding of our study was the negative impact of IgA hypogammaglobulinemia on response to vaccination. Other negative significant factors were treatment with anti-CD20 antibody at vaccination and vaccination within 18 months from HSCT. Our data indicate that HSCT recipients elicit a positive response to the BNT162b2 vaccine against SARS-CoV-2 when vaccinated at 6 months post-transplant, and vaccination should be offered to this patient population even within the post-pandemic COVID-19 era.

Prognostic Impact of Serum ß2-Microglobulin Levels in Hodgkin Lymphoma Treated with ABVD or Equivalent Regimens: A Comprehensive Analysis of 915 Patients.

The significance of serum beta-2 microglobulin (sß2m) in Hodgkin lymphoma (HL) is controversial. We analyzed 915 patients with HL, who were treated with ABVD or equivalent regimens with or without radiotherapy. Sß2m levels were measured by a radioimmunoassay (upper normal limit 2.4 mg/L). Sequential cutoffs (1.8-3.0 by 0.1 mg/L increments, 3.5 and 4.0 mg/L) were tested along with ROC analysis. The median sß2m levels were 2.20 mg/L and were elevated (>2.4 mg/L) in 383/915 patients (41.9%). Higher sß2m was associated with inferior freedom from progression (FFP) at all tested cutoffs. The best cutoff was 2.0 mg/L (10-year FFP 83% vs. 70%, p = 0.001), which performed better than the 2.4 mg/L cutoff ("normal versus high"). In multivariate analysis, sß2m > 2.0 mg/L was an independent adverse prognostic factor in the whole patient population. In multivariate overall survival analysis, sß2m levels were predictive at 2.0 mg/L cutoff in the whole patient population and in advanced stages. Similarly, sß2m > 2.0 mg/L independently predicted inferior HL-specific survival in the whole patient population. Our data suggest that higher sß2m is an independent predictor of outcome in HL but the optimal cutoff lies within the normal limits (i.e., at 2.0 mg/L) in this predominantly young patient population, performing much better than a "normal versus high" cutoff set at 2.4 mg/L.

A Case Report of Chronic Myelogenous Leukemia Presenting as Blastic Crisis with a T-Cell Acute Lymphoblastic Leukemia Phenotype: Awareness of a Rare Entity.

Chronic myelogenous leukemia at blast crisis with a T-cell phenotype (T-ALL CML-BC) at diagnosis, without any prior history of CML is extremely rare. After the introduction of tyrosine kinase inhibitors (TKIs), CML patients have a median survival comparable to general population and accelerated/blast crisis are rarely encountered. Most CML patients (80%) transform into acute myeloid leukemia and the rest into B-ALL. Anecdotal cases of Ph+ T-ALL, either de novo or in the context of CML-BC have been reported. Left shift in the blood, the presence of splenomegaly/extramedullary infiltration and the occurrence of BCR::ABL1 rearrangement in both the blastic population, as well as in the myeloid cell compartment are key points in differentiating de novo Ph+ T-ALL from T-ALL CML-BC. The latter is a rare entity, characterized by extramedullary disease, p210 transcript and clonal evolution. Lack of preceding CML does not rule out the diagnosis of T-ALL CML-BC. Prompt TKI treatment with ALL-directed therapy followed by allogeneic stem cell transplantation may offer long-term survival in this otherwise poor prognosis entity. In this paper, we describe a patient with T-ALL CML-BC at presentation, still alive 51 months after diagnosis and we offer a review of the literature on this rare subject. All clinical and laboratory features are provided in order to distinguish de novo Ph+ T-ALL from T-ALL CML-BC, underscoring the prognostic and therapeutic significance of such a differentiation.

Real-life Experience With Rituximab-CHOP Every 21 or 14 Days in Primary Mediastinal Large B-cell Lymphoma.

BACKGROUND/AIM: Primary mediastinal large B-cell lymphoma (PMLBCL) is an aggressive B-cell non-Hodgkin lymphoma (NHL), whose prognosis has greatly improved since the incorporation of the anti-CD20 monoclonal antibody rituximab into current therapeutic regimens. Evidence, however, on the optimal time interval between consecutive chemoimmunotherapy (CIT) cycles is still scarce. This study aimed to evaluate the efficacy outcomes of the more commonly administered 3-weekly regimens to the biweekly ones in a PMLBCL patients' population, who were mostly treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone every 21 days (R-CHOP-21) or R-CHOP-14. PATIENTS AND METHODS: We retrospectively studied our cohort of consecutively treated PMLBCL patients, focusing on their treatment density, in order to determine possible differences in treatment outcomes. RESULTS: CIT, in the form of both R-CHOP-21 as well as R-CHOP-14 (or similar regimens), is highly active in PMLBCL, with low rates of early treatment failure. In our cohort of patients, R-CHOP-14 did not result in a meaningful improvement of freedom from progression (FFP) or overall survival (OS). CONCLUSION: Both R-CHOP-14 and R-CHOP-21 are probably equally effective in PMLBCL, yet further, prospective, randomized studies are warranted to clarify whether dose-dense regimens can be associated with better disease control and long-term results.

Serum ferritin levels in previously untreated classical Hodgkin lymphoma: correlations and prognostic significance.

Serum ferritin (SF) is frequently elevated in classical Hodgkin lymphoma (cHL). We report on its prognostic significance in an unselected series of 529 cHL patients treated with state-of-the-art therapy. Higher baseline levels correlated with markers of advanced/aggressive disease. SF levels were significantly higher in male and older patients, those with high body mass index and mixed cellularity histology. The strongest correlation was recorded between SF and complement reactive protein (CRP) levels. Gender-specific SF cutoffs which provided the best discrimination in terms of freedom from progression (FFP) were identified. In multivariate analysis elevated SF levels, advanced stage and high lactate dehydrogenase (LDH) were independent prognostic factors of inferior FFP. SF also appears to retain independent prognostic significance for progression-free survival (PFS) but not for overall survival (OS). In conclusion, SF levels in cHL reflect disease activity and are associated with adverse patient outcomes.

Identification of Very Low-Risk Subgroups of Patients with Primary Mediastinal Large B-Cell Lymphoma Treated with R-CHOP.

BACKGROUND: R-CHOP can cure approximately 75% of patients with primary mediastinal large B-cell lymphoma (PMLBCL), but prognostic factors have not been sufficiently evaluated yet. R-da- EPOCH is potentially more effective but also more toxic than R-CHOP. Reliable prognostic classification is needed to guide treatment decisions. MATERIALS AND METHODS: We analyzed the impact of clinical prognostic factors on the outcome of 332 PMLBCL patients ≤65 years treated with R-CHOP ± radiotherapy in a multicenter setting in Greece and Cyprus. RESULTS: With a median follow-up of 69 months, 5-year freedom from progression (FFP) was 78% and 5-year lymphoma specific survival (LSS) was 89%. On multivariate analysis, extranodal involvement (E/IV) and lactate dehydrogenase (LDH) ≥2 times upper limit of normal (model A) were significantly associated with FFP; E/IV and bulky disease (model B) were associated with LSS. Both models performed better than the International Prognostic Index (IPI) and the age-adjusted IPI by Harrel's C rank parameter and Akaike information criterion. Both models A and B defined high-risk subgroups (13%-27% of patients [pts]) with approximately 19%-23% lymphoma-related mortality. They also defined subgroups composing approximately one-fourth or one-half of the patients, with 11% risk of failure and only 1% or 4% 5-year lymphoma-related mortality. CONCLUSION: The combination of E/IV with either bulky disease or LDH ≥2 times upper limit of normal defined high-risk but not very-high-risk subgroups. More importantly, their absence defined subgroups comprising approximately one-fourth or one-half of the pts, with 11% risk of failure and minimal lymphoma-related mortality, who may not need more intensive treatment such as R-da-EPOCH. IMPLICATIONS FOR PRACTICE: By analyzing the impact of baseline clinical characteristics on outcomes of a large cohort of patients with primary mediastinal large B-cell lymphoma homogeneously treated with R-CHOP with or without radiotherapy, we developed novel prognostic indices which can aid in deciding which patients can be adequately treated with R-CHOP and do not need more intensive regimens such as R-da-EPOCH. The new indices consist of objectively determined characteristics (extranodal disease or stage IV, bulky disease, and markedly elevated serum lactate dehydrogenase), which are readily available from standard initial staging procedures and offer better discrimination compared with established risk scores (International Prognostic Index [IPI] and age-adjusted IPI).

Real-life experience with the combination of polatuzumab vedotin, rituximab, and bendamustine in aggressive B-cell lymphomas.

Transplant-ineligible relapsed/refractory (rr) diffuse large B-cell lymphoma (DLBCL) patients represent an unmet medical need. Polatuzumab vedotin (Pola), an anti-CD79b antibody-drug-conjugate (ADG), with bendamustine- rituximab(BR) has recently gained approval for these patients, both in the USA and Europe, based on the GO29365 phase IIb trial. Real-life data with Pola are extremely limited. We report the outcomes of 61 Greek patients, who received Pola-(B)R mainly within a compassionate use program. Treatment was given for up to six 21-day cycles. Bendamustine was omitted in three cases due to previous short-lived responses. Fourty-nine rrDLBCL(efficacy cohort-EC) and 58 rr aggressive B-NHL (safety cohort-SC) patients received at least 1 Pola-BR cycle. Twenty-one (43%) patients of the EC responded with 12/49 (25%) CR and 9/49 (18%) PR as best response. Median progression-free survival, overall survival and duration of response were 4.0, 8.5, and 8.5 months respectively, while 55% of patients experienced a grade ≥3 adverse event, mainly hematologic. Treatment discontinuations and death during treatment were mainly due to disease progression. Twenty-two (41%) patients received further treatment; 11/22 are still alive, including one after CAR-T cells, and two after stem cell transplantation. Our data confirm that Pola-BR is a promising treatment for rrDLBCL patients, inducing an adequate response rate with acceptable toxicity. Pola-BR could be used as bridging therapy before further consolidative treatments.

Positron emission tomography after response to rituximab-CHOP in primary mediastinal large B-cell lymphoma: impact on outcomes and radiotherapy strategies.

End-of-treatment (EoT) PET/CT is used as a guide to omit radiotherapy (RT) patients with primary mediastinal large B-cell lymphoma (PMBCL). We present the mature and extended results of a retrospective study evaluating the prognostic significance of EoT-PET/CT after adequate response to R-CHOP. Among 231 consecutive PMLBCL patients, 182 underwent EoT-PET/CT and were evaluated according to the Deauville 5-point scale (D5PS) criteria. Freedom from progression (FFP) was measured from the time of PET/CT examination. Among 182 patients, 72 (40%) had D5PS score 1 (D5PSS-1), 33 (18%) had 2, 28 (15%) had 3, 29 (16%) had 4, and 20 (11%) had 5. The 5-year FFP was 97, 94, 92, 82, and 44% for D5PSS-1, D5PSS-2, D5PSS-3, D5PSS-4, and D5PSS-5, respectively. Among 105 patients with unequivocally negative PET/CT (D5PSS-1/D5PSS-2), 49 (47%) received RT (median dose 3420 cGy) and 56 (53%) did not with relapses in 0/49 vs. 4/56 patients (2 mediastinum and 2 isolated CNS relapses).The 5-year FFP for those who received RT or not was 100% versus 96%, when isolated CNS relapses were censored (p = 0.159). Among D5PSS-3 patients (27/28 irradiated-median dose 3600 cGy), the 5-year FFP was 92%. The 5-year FFP for D5PSS-4 and D5PSS-5 was 82 and 44%; 44/49 patients received RT (median dose 4000 and 4400 cGy for D5PSS-4 and D5PSS-5). Our study supports the omission of RT in a sizeable fraction of PET/CT-negative patients and definitely discourages salvage chemotherapy and ASCT in patients with PMLBCL who conventionally respond to R-CHOP, solely based on PET/CT positivity in the absence of documented progressive or multifocal disease. The persistence of positive PET/CT with D5PSS < 5 after consolidative RT should not trigger the initiation of further salvage chemotherapy in the absence of conventionally defined PD.

The Significance of PET/CT in the Initial Staging of Hodgkin Lymphoma: Experience Outside Clinical Trials.

AIM: To examine the real-life impact of baseline positron-emission tomography/computed tomography (PET/CT) in Hodgkin lymphoma (HL). PATIENTS AND METHODS: A total of 162 consecutive patients with HL were retrospectively studied. RESULTS: Disease was up-staged in 26 patients (16%) and down-staged in 9 (6%). However, treatment strategy was modified in only 10 patients (6% of total). Involved field radiotherapy was delineated according to PET/CT in 36/66 patients (59%). These treatment modifications did not significantly affect outcome. Moreover, three potent prognostic parameters were identified: the number of involved sites, maximum standardized uptake value (SUVmax), and the product of SUVmax and maximal largest lesion diameter, as a surrogate of total lesion glycolysis. All three significantly correlated with 5-year freedom from disease progression p=0.004, p=0.009 and p=0.04, respectively). CONCLUSION: Baseline PET/CT findings may lead to treatment modification in <15% of patients with HL without a significant impact on outcome. Certain PET/CT parameters have potent prognostic significance.

Prognostic Implication of the Absolute Lymphocyte to Absolute Monocyte Count Ratio in Patients With Classical Hodgkin Lymphoma Treated With Doxorubicin, Bleomycin, Vinblastine, and Dacarbazine or Equivalent Regimens.

Low absolute lymphocyte count (ALC) to absolute monocyte count (AMC) ratio (ALC/AMC) is an independent prognostic factor in Hodgkin lymphoma (HL), but different cutoffs (1.1, 1.5, and 2.9) have been applied. We aimed to validate the prognostic significance of ALC/AMC in 537 homogenously treated (doxorubicin, bleomycin, vinblastine, and dacarbazine or equivalents ± radiotherapy) classical HL patients at various cutoffs. The median ALC/AMC was 2.24 (0.44-20.50). The median AMC was 0.653 × 10(9)/L (0.050-2.070). Lower ALC/AMC was associated with established markers of adverse prognosis. In total, 477 (89%), 418 (78%), and 189 (35%) patients had an ALC/AMC ratio of ≥1.1, ≥1.5, and ≥2.9; respectively; 20% had monocytosis (≥0.9 × 10(9)/L). Ten-year time to progression (TTP) was 77% versus 55% for patients with ALC/AMC ≥1.1 and <1.1 (p = .0002), 76% versus 68% for ALC/AMC ≥1.5 and <1.5 (p = .049), 77% versus 73% for ALC/AMC ≥2.9 and <2.9 (p = .35), and 79% versus 70% for ALC/AMC ≥2.24 and <2.24 (p = .08), respectively. In stages ΙΑ/ΙΙΑ and in patients ≥60 years old, ALC/AMC had no significant effect on TTP. In advanced stages, ALC/AMC was significant only at the cutoff of 1.1 (10-year TTP 67% vs. 48%; p = .016). In younger, advanced-stage patients, the differences were more pronounced. In multivariate analysis of TTP, ALC/AMC < 1.1 (p = .007) and stage IV (p < .001) were independent prognostic factors; ALC/AMC was independent of International Prognostic Score in another model. ALC/AMC was more predictive of overall survival than TTP. At the cutoff of 1.1, ALC/AMC had independent prognostic value in multivariate analysis. However, the prognostically inferior group comprised only 11% of patients. Further research is needed prior to the widespread use of this promising marker.

Cytomegalovirus meningoencephalitis after rituximab treatment for primary central nervous system lymphoma.

The efficacy and safety of rituximab against B-cell lymphomas is well established. However, there has been an increased incidence of infectious complications after rituximab treatment, mostly hepatitis B reactivation and progressive multifocal leukoencephalopathy. This is the case of a 67-year-old patient with primary central nervous system lymphoma, who developed cytomegalovirus meningoencephalitis after receiving high-dose chemotherapy and rituximab. As there was no evidence of lymphoma relapse or additional immunosuppression, besides his previous treatment, an association between rituximab and cytomegalovirus meningoencephalitis cannot be ruled out.

Cessation of tyrosine kinase inhibitors in patients with chronic-phase chronic myelogenous leukemia following durable complete molecular response: a single center facing the dilemma.

Tyrosine kinase inhibitors (TKIs), namely imatinib mesylate (IM) and recently approved second-generation TKIs dasatinib and nilotinib, are currently considered the treatment of choice for newly-diagnosed chronic phase chronic myelogenous leukemia (CP-CML). Although treatment with TKIs has not yet been proven curative, it certainly accomplishes a sustained control of the disease in the vast majority of patients. More than a decade after the successful launching of IM in first-line treatment of CP-CML and the subsequent introduction of second-generation TKIs in this setting, the question of the possibility of TKI cessation in a specific subset of patients has emerged. Side-effects of TKIs, along with some patients' wish to abandon the drugs and the rising financial burden upon healthcare systems, have led to the dilemma whether IM can be safely withdrawn after achieving deep molecular remissions and which patients are suitable for this discontinuation. We examined the data of our patients with CML in search of potential canditates for cessation of TKI therapy and identified their characteristics. We also performed a thorough review of the relevant literature. Eight out of fifty patients were discriminated on grounds of sustained complete molecular response (CMR) exceeding 12 months, most of them with a low or intermediate Sokal score at diagnosis. The median interval from IM initiation to CMR was almost 2 years and the median duration of detected CMR reached 6.5 years. Based on the promising results of prospective clinical trials reporting successful cessation of treatment with TKIs on selected subgroups of patients, we decided to proceed to interruption of therapy in the specific subset of our patients and closely monitor their response.

Treatment of splenic marginal zone lymphoma with rituximab monotherapy: progress report and comparison with splenectomy.

BACKGROUND: Treatment of splenic marginal zone lymphoma (SMZL) patients is not standardized. Recent data suggest that rituximab is highly effective and could be considered as initial therapy. AIM: To assess the efficacy of rituximab monotherapy in a large series of patients with SMZL and compare these results with splenectomy results. METHODS: The studied population included 85 patients. Fifty-eight received rituximab at a dose of 375 mg/m2 per week for 6 weeks as induction followed by maintenance at the same dose every 2 months for 1-2 years, whereas 27 patients were treated using splenectomy only. RESULTS: The overall response rate to rituximab 2 months after the end of induction was 95% (complete response [CR], 45%; unconfirmed CR, 26%; partial response, 24%). The median times to hematologic and clinical response were 2 weeks and 3 weeks, respectively. Forty-three of 55 patients already completed the maintenance phase: 28 sustained their initial response, 14 improved their response, and one progressed. Eighty-five percent of splenectomized patients responded, and two were treated with rituximab as consolidation after splenectomy and achieved a CR. The 5-year overall and progression-free survival (PFS) rates for rituximab-treated and splenectomized patients were 92% and 77% (p = .09) and 73% and 58% (p = .06), respectively. Furthermore, maintenance therapy with rituximab resulted in a longer duration of response (at 5 years, PFS was 84% for patients receiving maintenance and 36% for patients without maintenance, p <.0001). CONCLUSIONS: Rituximab is a very effective and well-tolerated therapy and may be substituted for splenectomy as the first-line treatment of choice for patients with SMZL.