Prognostic impact of persistent cytogenetic abnormalities at complete remission in adult patients with acute lymphoblastic leukemia

In acute myelogenous leukemia, the persistent detection of abnormal cytogenetics at complete remission (ACCR) is associated with inferior outcomes. However, the prognostic significance of ACCR in adult patients with acute lymphoblastic leukemia (ALL) is unknown. We evaluated 272 adult patients with ALL and abnormal cytogenetics at baseline who were treated with frontline induction chemotherapy, achieved complete remission (CR) and had cytogenetic analysis performed at the time of CR. ACCR was observed in 26 patients (9.6%). Median relapse‐free survival was 22 months (95% CI, 12 months to not reached) for patients with ACCR vs. 48 months (range, 30–125 months) in patients with normal cytogenetics at CR (NCCR; P = 0.31). Median overall survival also did not differ significantly between the ACCR (99 months [range, 17 months to not reached]) and NCCR groups (67 months [range, 47 months to not reached], P = 0.86). The specificity of ACCR for minimal residual disease (MRD) positivity by multi‐parameter flow cytometry (MFC) was 43%, and there was overall poor correlation between these two methods for the detection of residual disease. When patients were stratified by MRD status, the presence or absence of persistent cytogenetic abnormalities at CR did not add additional prognostic information. This study suggests that there is poor association between MRD assessment by MFC and the presence or absence of cytogenetic abnormalities at CR in adult patients with ALL. ACCR was not associated with adverse outcomes in ALL and did not add additional prognostic information when MRD status by MFC was known. Am. J. Hematol. 91:385–389, 2016. © 2016 Wiley Periodicals, Inc.     

Histiocytic lymphoma fifteen years following remission of acute lymphoblastic leukemia

A 19-yr-old female presented with diffuse histiocytic lymphoma after a 15-yr remission of acute lymphoblastic leukemia. All treatment had been discontinued 7 yr before the onset of the lymphoma. The possible relationships of these two neoplasms are discussed.     

Unrelated donor transplants in adults with Philadelphia-negative acute lymphoblastic leukemia in first complete remission

We report the retrospective outcomes of unrelated donor (URD) transplants in 169 patients with acute lymphoblastic leukemia (ALL) in first complete remission (CR1) who received transplants between 1995 and 2004. Median age was 33 years (range, 16-59 years). A total of 50% had a white blood cell count (WBC) more than 30 x 10⁹/L, 18% extramedullary disease, 42% achieved CR more than 8 weeks from diagnosis, 25% had adverse cytogenetics, and 19% had T-cell leukemia. A total of 41% were HLA well-matched, 41% partially matched with their donors, and 18% were HLA-mismatched. At 54-month median follow-up, incidences of acute grade 2-IV, III to IV, and chronic graft-versus-host disease were 50%, 25%, and 43%, respectively. Five-year treatment-related mortality (TRM), relapse, and overall survival were 42%, 20%, and 39%, respectively. In multivariate analyses, TRM was significantly higher with HLA-mismatched donors and T-cell depletion. Relapse risk was higher if the diagnostic WBC was more than 100 x 10⁹/L. Factors associated with poorer survival included WBC more than 100 x 10⁹/L, more than 8 weeks to CR1, cytomegalovirus seropositivity, HLA mismatching, and T-cell depletion. Nearly 40% of adults with ALL in CR1 survive 5 years after URD transplantation. Relapse risks were modest; TRM is the major cause of treatment failure. Selecting closely HLA-matched URD and reducing TRM should improve results.     

Marrow transplantation for patients with acute lymphoblastic leukemia in first marrow remission

Forty-six patients with acute lymphoblastic leukemia (ALL) in first marrow remission underwent allogeneic marrow transplantation between August 1976 and June 1985. Thirty-four patients had no extramedullary disease after remission induction and 12 had extramedullary relapses prior to or at the time of marrow grafting. The conditioning regimen included cyclophosphamide followed by total body irradiation, 9.2-15.75 Gy, administered as a single dose or in six or seven daily fractions. Marrow donors were genotypically HLA-identical siblings. Methotrexate was given as prophylaxis for graft-versus-host disease (GVHD). Forty-four patients had marrow engraftment. The incidence of grades II-IV acute GVHD was 52%. Clinical chronic GVHD occurred in 21 patients. Eighteen patients are alive 1-9 years (median = 4.2 years) after marrow grafting, 15 of whom are in continuous complete remission. The estimated probability of relapse within 2 years (+/- standard error) is 41 +/- 9% and the probability of relapse-free survival at 5 years is 28 +/- 7%. Major causes of death were recurrent leukemia, acute GVHD and interstitial pneumonia. Actuarial probabilities of survival, relapse and disease-free survival were not significantly different between those patients who did and those who did not have extramedullary disease after attaining first marrow remission.     

Allogeneic bone marrow transplantation for high-risk acute lymphoblastic leukemia during first complete remission

Fifty-three patients with high-risk acute lymphoblastic leukemia (ALL) under age 50 with a histocompatible sibling donor received high-dose radiochemotherapy followed by allogeneic bone marrow transplantation (BMT). The high-risk factors used to identify the patients were: white blood cell count at initial presentation, cytogenetic abnormalities, age, extramedullary leukemic infiltration, and time from initial therapy to complete remission. Patients with one or more of the above risk factors who received BMT have a disease-free survival of 61% with a median follow-up of 66 months (range 11 months to 10.6 years), and an actuarial relapse rate of 10%. This study demonstrates that patients with high-risk ALL achieve a significant disease-free survival and cure rate with the use of allogeneic fully matched sibling BMT. However, a properly designed prospective study comparing the outcome of BMT with the best currently available chemotherapy data is required to define the ultimate role of BMT in this group of patients.     

Allogeneic or autologous bone marrow transplantation for acute lymphoblastic leukemia in first complete remission

Forty-seven patients with high risk acute lymphoblastic leukemia (ALL) received an allogeneic (allo) or autologous (auto) bone marrow transplant (BMT). Patients in both groups were comparable in terms of age, initial presentation of ALL and induction chemotherapy. Allo patients were transplanted earlier (median 3 months after CR) than auto patients (median 6.5 months after CR). Auto patients received more consolidation chemotherapy before BMT. All patients received total body irradiation 2.2 Gy/day x 5 days after cyclophosphamide 60 mg/kg x 2 (18 allo and five auto) or melphalan 140 mg/m2 (seven allo and 17 auto). Prevention of graft-versus-host disease (GVHD) was by conventional immunosuppression in 17 patients and T cell depletion in eight. Seven patients (28%) developed moderate to severe acute GVHD. Auto marrow was treated in vitro in each case. Seven patients died in CR from BMT complications (five allo and two auto). The probability of relapse was 9% for patients receiving allo BMT and 52% for patients receiving auto BMT (p less than 0.01). The disease-free survival was 71% for allo BMT and 40% for auto BMT (p = NS). Early BMT is an effective form of consolidation for high risk patients with ALL in first CR. An allogeneic anti-leukemia effect was demonstrated in this study.     

Efficacy of imatinib mesylate as maintenance therapy in adults with acute lymphoblastic leukemia in first complete remission

Seven Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) patients in first complete remission received maintenance therapy with imatinib alone. Two-year progression-free survival was 75%. Quantitative polymerase-chain-reaction (qPCR) monitoring of BCR-ABL showed that: (i) persisting molecular complete response (CR) was associated with long-lasting CR; (ii) molecular relapse did not invariably mean hematologic relapse; (iii) only the wide and rapid increment of BCR-ABL values was predictive of leukemia relapse.     

Acute hemorrhagic leukoencephalitis in patients with acute myeloid leukemia in hematologic complete remission

The authors describe the cases of three patients affected by acute myeloid leukemia, in complete remission, who rapidly developed neurologic symptoms leading to death. Neither clinical characteristics, nor radiological or microbiological procedures, allowed an etiological diagnosis of the neurologic syndrome. Post-mortem examination of the brain showed both macroscopic and microscopic findings compatible with acute hemorrhagic leukoencephalitis. The difficulty in distinguishing this entity from other CNS disease-related complications (e.g. leukemia infiltration, drug toxicity, hemorrhages) should not lead to an underestimation of the true incidence of this complication. We believe that with more attention to the possibility of this complication there would probably be both a greater possibility of collecting clinical informations about the real impact of this dramatic disease and a stronger hope of finding the right treatment for it.     

Immunoglobulin gene rearrangements in remission bone marrow specimens from patients with acute lymphoblastic leukemia

Recombinant DNA probes for the joining (JH) segment of the immunoglobulin heavy chain gene were used to detect molecular rearrangements of this gene in the DNA of bone marrow cells obtained during remission of acute lymphoblastic leukemia (ALL). This molecular approach was optimized and found to exceed the sensitivity of conventional morphologic screening for detecting residual leukemia cells; one leukemic cell in 500 normal nucleated bone marrow cells was easily detected using this approach. In the present study, bone marrow from three of seven patients in complete clinical remission (defined morphologically) contained leukemic cells in these proportions. This analysis may be of use in evaluating the status of clinical remission in selected ALL patients.     

Spontaneous complete remission in a patient with acute monocytic leukemia

A spontaneous complete remission was observed in a 47-year-old female with acute monocytic leukemia. Resolution of all abnormalities, including systemic papule, thrombocytopenia, increased numbers of immature monocytoid cells in the peripheral blood and bone marrow, elevation of serum lysozyme and LDH, and trisomy 8 on chromosome analysis, occurred without any treatment. Moreover, the remission was not associated with any infection or blood transfusion, and is persistent for 12-month duration.     

Long-term follow-up of residual disease in acute lymphoblastic leukemia patients in complete remission using clonogeneic IgH probes and the polymerase chain reaction

We sequentially studied bone marrow (BM) samples of 25 patients in complete remission of an acute lymphoblastic leukemia (ALL) using a simplified polymerase chain reaction (PCR) strategy (direct use of the PCR product as a clonogenic probe recognizing rearranged Ig heavy chain sequences) as a first approach. BM aspirates were serially investigated after obtention of a complete response. When sensitivity was less than 1:10(4), the PCR fragment was sequenced and a specific oligonucleotide was synthetized and used as a probe (five cases). Cases in which minimal residual disease (MRD) became undetectable were cross- controlled using either TCR delta rearrangement or a specific translocation to circumvent the problem of false-negative results arising from clonal evolution. The median follow-up was 30 months (3 to 51 months). Within the first 3 months of complete remission, MRD was detectable in 22 of 23 investigated patients and remained so in 19 of 21 patients examined at 6 months, regardless of the long-term clinical outcome. In patients remaining in complete remission at 30 months or more, two patterns of MRD emerged during the follow-up. Either it continuously decreased to ultimately become undetectable (five patients) or remained detectable (five patients) with an increase after discontinuation of treatment in two. In the eight patients who relapsed, MRD persisted throughout the clinical course, and eventually increased 3 to 12 months before relapse was clinically detectable. In one case, clonal evolution of the VDJ heavy chain region was observed and recurrence of MRD shown by the use of TCR delta rearrangement as a control. We conclude that the use of this simplified methodology is a valuable tool for the follow-up of MRD in a majority of ALL patients, though in a few cases, sequencing needs to be performed to achieve a relevant sensitivity. The possibility of clonal evolution requires a cross-control of any sample becoming negative whatever the initial rearrangement used to generate a probe. In patients on therapy, sequential search for MRD seems to be a good tool for predicting the long-term outcome. In addition, patients remaining positive at the time treatment is discontinued or with a high tumor burden after a few months therapy may be at a higher risk of subsequent relapse, although a longer follow-up is needed to answer this question.     

Lymphocytic infundibuloneurohypophysitis during the first remission in acute lymphoblastic leukemia

A 15-year-old girl developed acute lymphoblastic leukemia (ALL). The patient was treated according to the 13th protocol of the Tokyo Children's Cancer Study Group, and thereafter remained free of disease. However, at the age of 20, she complained of polyuria, polydipsia and amenorrhea. Hematological or meningeal relapse was ruled out on the basis of clinical and laboratory findings. The plasma concentrations of GH, TSH, LH, FSH, ACTH and ADH were low or below the detectable limits. There was no increase in urine osmolarity after water deprivation. Arginine, LH-RH, TRH and CRH tolerance tests revealed no or low responses of GH, LH/FSH, TSH, and ACTH/cortisol, respectively. Magnetic resonance imaging demonstrated thickening of the pituitary stalk, which was homogeneously enhanced by gadolinium administration. A biopsy specimen showed fibrosis and infiltration of CD8-positive T lymphocytes in a portion of the pituitary stalk, whereas the adenohypophysis was normal. In addition, no leukemic cells were observed in the samples. Thus, a diagnosis of lymphocytic infundibuloneurohyophysitis (LIN) was established. All the symptoms were improved by treatment with hydrocortisone, L-thyroxine, desamino-8-d-arginine vasopressin, estrogen and gestagen. This is the first reported case of ALL complicated by LIN.     

Marrow transplantation for children with acute lymphoblastic leukemia in second remission

Fifty-seven children between the ages of 3 and 17 years with acute lymphoblastic leukemia (ALL) in chemotherapy-induced second bone marrow remission were given cyclophosphamide, total body irradiation, and bone marrow transplants from HLA-matched donors. Sixteen died of transplant- related complications. Eighteen relapsed between 56 and 833 days after transplantation, and 16 died of leukemia. Two survive in remission off treatment following chemotherapy. Twenty-three survive in continuous remission from 1.4 to 10.4 years after transplantation and the actuarial analysis shows disease-free survival of 40% with a plateau extending from 2.5 to 10.4 years.